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Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

L Galluzzi, J M Bravo-San Pedro, I Vitale and 97 more

Cell Death & Differentiation · 2014 · Review

doi:10.1038/cdd.2014.137

Abstract

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

1Defining life and death is more problematic than one would guess. In 1838, the work of several scientists including Matthias Jakob Schleiden, Theodor Schwann and Rudolf Carl Virchow culminated in the so-called ‘cell theory', postulating that: (1) all living organisms are composed of one or more cells; (2) the cell is the basic unit of life; and (3) all cells arise from pre-existing, living cells. Only a few decades later (in 1885), Walter Flemming described for the first time some of the morphologic features that have been largely (but often inappropriately) used to define apoptosis throughout the past four decades.,,

2A corollary of the cell theory is that viruses do not constitute bona fide living organisms. However, the discovery that the giant Acanthamoeba polyphaga mimivirus can itself be infected by other viral species has casted doubts on this point.,, Thus, the features that underlie the distinction between a living and an inert entity remain a matter of debate. Along similar lines, defining the transition between an organism's life and death is complex, even when the organism under consideration is the basic unit of life, a cell. From a conceptual standpoint, cell death can obviously be defined as the permanent degeneration of vital cellular functions. Pragmatically speaking, however, the precise boundary between a reversible alteration in homeostasis and an irreversible loss of cellular activities appears to be virtually impossible to identify. To circumvent this issue, the Nomenclature Committee on Cell Death (NCCD) previously proposed three criteria for the identification of dead cells: (1) the permanent loss of the barrier function of the plasma membrane; (2) the breakdown of cells into discrete fragments, which are commonly referred to as apoptotic bodies; or (3) the engulfment of cells by professional phagocytes or other cells endowed with phagocytic activity.,,

3However, the fact that a cell is engulfed by another via phagocytosis does not imply that the cell-containing phagosome fuses with a lysosome and that the phagosomal cargo is degraded by lysosomal hydrolases.,, Indeed, it has been reported that engulfed cells can be released from phagosomes as they preserve their viability, at least under some circumstances. Thus, the NCCD recommends here to consider as dead only cells that either exhibit irreversible plasma membrane permeabilization or have undergone complete fragmentation. A compendium of techniques that can be used to quantify these two markers of end-stage cell death in vitro and in vivo goes beyond the scope of this review and can be found in several recent articles.,,,,,,,,,

4Importantly, cell death instances can be operationally classified into two broad, mutually exclusive categories: ‘accidental' and ‘regulated'. Accidental cell death (ACD) is caused by severe insults, including physical (e.g., elevated temperatures or high pressures), chemical (e.g., potent detergents or extreme variations in pH) and mechanical (e.g., shearing) stimuli, is virtually immediate and is insensitive to pharmacologic or genetic interventions of any kind. The NCCD thinks that this reflects the structural disassembly of cells exposed to very harsh physicochemical conditions, which does not involve a specific molecular machinery. Although ACD can occur in vivo, for instance as a result of burns or traumatic injuries, it cannot be prevented or modulated and hence does not constitute a direct target for therapeutic interventions.,,, Nonetheless, cells exposed to extreme physicochemical or mechanical insults die while releasing elevated amounts of damage-associated molecular patterns (DAMPs), that is, endogenous molecules with immunomodulatory (and sometimes cytotoxic) activity. Some DAMPs can indeed propagate an unwarranted cytotoxic response (directly or upon the involvement of innate immune effectors) that promotes the demise of local cells surviving the primary insult.,,,, Intercepting DAMPs or blocking DAMP-ignited signaling pathways may mediate beneficial effects in a wide array of diseases involving accidental (as well as regulated) instances of cell death.,

5At odds with its accidental counterpart, regulated cell death (RCD) involves a genetically encoded molecular machinery., Thus, the course of RCD can be altered by means of pharmacologic and/or genetic interventions targeting the key components of such a machinery. Moreover, RCD often occurs in a relatively delayed manner and is initiated in the context of adaptive responses that (unsuccessfully) attempt to restore cellular homeostasis.,,,, Depending on the initiating stimulus, such responses can preferentially involve an organelle, such as the reticular unfolded protein response, or operate at a cell-wide level, such as macroautophagy (hereafter referred to as autophagy).,,,,, Thus, while ACD is completely unpreventable, RCD can be modulated (at least to some extent, see below) not only by inhibiting the transduction of lethal signals but also by improving the capacity of cells to mount adaptive responses to stress.,,,,, Importantly, RCD occurs not only as a consequence of microenvironmental perturbations but also in the context of (post-)embryonic development, tissue homeostasis and immune responses.,,, Such completely physiologic instances of RCD are generally referred to as ‘programmed cell death' (PCD) (Figure 1).,

6For the purpose of this discussion, it is useful to keep in mind the distinction that is currently made between the initiation of RCD and its execution. The term execution is generally used to indicate the ensemble of biochemical processes that truly cause the cellular demise. Conversely, initiation is commonly used to refer to the signal transduction events that activate executioner mechanisms. Thus, the activation of caspase-8 (CASP8) in the course of FAS ligand (FASL)-triggered apoptosis is widely considered as an initiator mechanism, whereas the consequent activation of caspase-3 (CASP3) is categorized as an executioner mechanism (see below).,,,

7Here, the NCCD formulates a set of recommendations to discriminate between essential and accessory aspects of RCD, that is, between those that etiologically mediate its occurrence and those that change its kinetics or morphologic and biochemical manifestations.

Morphologic Aspects of Cell Death

8The early classifications of cell death were purely morphologic, owing to obvious technical limitations., In 1964, the American biologist Richard A Lockshin was the first to thoroughly describe the demise of intersegmental muscles in developing silk moths, a seminal contribution to the modern understanding of PCD. A few years later, in 1972, the Australian pathologist John F Kerr together with his Scottish colleagues Andrew H Wyllie and Alastair R Currie coined the term ‘apoptosis' (from the ancient Greek, meaning ‘falling off') to indicate a morphologically stereotyped form of cellular demise characterized by cytoplasmic shrinkage, chromatin condensation initiating at the nuclear membrane (marginalization) and then involving the whole nucleus (pyknosis), nuclear fragmentation (karyorrhexis), minimal alterations of other organelles and a peculiar ‘boiling-like' process (blebbing) culminating in the formation of a few discrete corpses that initially retain plasma membrane integrity (apoptotic bodies).,, Soon thereafter, the first ‘formal' classification of cell death differentiated between: (1) type I cell death (apoptosis), manifesting with the morphologic features described above; (2) type II cell death (autophagy), featuring an extensive vacuolization of the cytoplasm; and (3) type III cell death (necrosis), exhibiting neither apoptotic nor autophagic characteristics., Such a ‘visual catalog' has dominated the field of cell death research for decades. Nonetheless, the NCCD views it as an oversimplification and considers it rather misleading, for several reasons.

9First, when this classification was formulated, necrosis (as defined by morphologic features) was considered as a strict equivalent of ACD, whereas apoptosis (as defined by morphologic features) was viewed as the sole programmed subroutine of cell death. Along similar lines, apoptosis was misconceived as an immunologically silent, if not tolerogenic, cell death modality., It is now clear that PCD does not always manifest with an apoptotic morphotype and does not necessarily fail to induce inflammatory or immune responses. For instance, the degradation of Drosophila melanogaster salivary glands and larval midgut relies on PCD manifesting with a type II morphology,,,,,,,, whereas the remodeling of bones at the growth plates is associated with type III-like features. Moreover, specific inducers are capable of promoting a variant of RCD that displays an apoptotic morphotype, yet is capable of activating adaptive immune responses., These observations indicate that morphologic and functional aspects of cell death are not necessarily linked to each other.

10Second, the negative morphologic definition of necrosis as a cell death modality that fails to exhibit apoptotic or autophagic features has been reconsidered., Indeed, necrosis can manifest with a stereotyped panel of features, including a generalized swelling of the cytoplasm, which acquires a translucent aspect, and organelles (oncosis), as well as a peculiar alteration of chromatin (condensation into small and irregular patches) and the nuclear membrane (dilatation). The evolution of the morphologic characterization of necrosis reflects the relatively recent discovery that RCD can also manifest with a necrotic aspect (see below).

11Third, the use of the term ‘autophagic cell death' has been a matter of intense debate. Such an expression was coined based on morphologic considerations (i.e., the appearance of autophagic vacuoles in the course of type II cell death) only, but it soon became misused to imply that the molecular machinery of autophagy would actively contribute to the cellular demise. The NCCD strongly recommends the use of the expression ‘autophagic cell death' from a functional perspective only, that is, to indicate a cell death subroutine that is limited or delayed by the pharmacologic or genetic inhibition of the autophagic machinery (see below).,

12Fourth, many instances of RCD present both apoptotic and necrotic traits. Moreover, several pharmacologic agents and genetic interventions designed to inhibit the execution of cell death often fail to do so when administered in a therapeutic (as opposed to prophylactic) manner, at least in the mammalian system, yet efficiently change its morphology.,,,,,,,,,,,,, This applies to N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethylketone (Z-VAD-fmk) and (3S)-5-(2,6-difluorophenoxy)-3-[[(2S)-3-methyl-1-oxo-2-[(2-quinolinylcarbonyl)amino]butyl]amino]-4-oxo-pentanoic acid hydrate (Q-VD-OPh), two broad-spectrum caspase inhibitors that have been widely investigated in the late 1990s as a means to mediate clinically relevant cytoprotection.,,, Z-VAD-fmk and Q-VD-OPh prevent the appearance of several morphologic markers of apoptosis, including nuclear pyknosis and blebbing (which rely on caspases),, yet fail to limit stimulus-dependent cell death if administered in therapeutic settings (i.e., after the cell death inducer).,,, Thus, caspase inhibition most often results in a shift from an overtly apoptotic to a mixed or necrotic cell death morphology., Conversely, both necrostatin 1 (Nec-1), a highly specific small inhibitor of the enzymatic activity of receptor-interacting protein kinase 1 (RIPK1), and geldanamycin, which targets heat-shock protein 90 kDa alpha (cytosolic), class A member 1 (HSP90AA1), have been demonstrated to shift the necrotic morphotype of RCD induced by tumor necrosis factor (ligand) superfamily, member 10 (TNFSF10, best known as TNF-related apoptosis-inducing ligand, TRAIL) at slightly acidic pH to an apoptotic one. A similar morphologic shift has been observed in cells succumbing to tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A, best known as tumor necrosis factor receptor 1, TNFR1) ligation in the presence of geldanamycin and in the absence of RIPK1 or one of its downstream targets, that is, receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL)., Also, cells exposed to DNA-alkylating agents in the presence of poly(ADP-ribose) polymerase 1 (PARP1) inhibitors die while manifesting an apoptotic, rather than a necrotic, morphology., Conversely, the introduction of a non-cleavable PARP1 variant appears to convert the apoptotic phenotype of cells succumbing to FAS ligation into a necrotic one. Possibly, this reflects the ability of PARP1, an NAD+-dependent enzyme initially characterized for its role in DNA repair and the DNA damage response,, to provoke an abrupt decline in intracellular ATP levels (secondary to NAD+ depletion), hence blocking various morphologic manifestations of apoptosis.,,,,, Such a morphologic shift, however, does not appear to stem from the inhibition of caspases, because neither the catalytic functions nor the activation of these proteases require ATP (which should not be confounded with deoxy-ATP, see below).,,,

13In summary, the morphologic manifestations of cell death can easily be altered in the absence of bona fide cytoprotection, casting doubts on the actual value of morphology-based classifications of cell death.

Biochemical Manifestations of Cell Death

14In 2012, the NCCD proposed to abandon the morphologic catalog of cell death instances in favor of a new classification based on quantifiable biochemical parameters. In substitution, the NCCD identified the main molecular events associated with specific cell death subroutines as well as the pharmacologic and/or genetic interventions that may be used to discriminate between various instances of cell death in experimental settings, in vitro and in vivo.

15Since then, our comprehension of specific RCD modalities has progressed significantly. Thus, while no paradigm-breaking discoveries have been made on the regulation and execution of caspase-dependent RCD instances (which most often display an apoptotic morphology), profound insights have been obtained into the mechanisms underlying cases of RCD that do not depend on caspases and generally manifest with necrotic features.,,, This notion began to emerge in the late 1980s, but became widely accepted only two decades later, owing to the milestone discoveries of Peter Vandenabeele,,,,, Jurg Tschopp and Junying Yuan,,, and to the characterization of the key role played by peptidylprolyl isomerase F (PPIF, best known as cyclophilin D, CYPD) in necrotic instances of RCD.,,, The identification of a genetically encoded machinery that promotes RCD with necrotic features generated an intense wave of investigation that has not yet come to an end.,,,

16From a biochemical standpoint, apoptosis is defined as a caspase-dependent variant of RCD., Other events commonly associated with apoptosis, such as the exposure of phosphatidylserine on the outer leaflet of the plasma membrane, are indeed less universal and more context-dependent,,, than previously thought. Apoptosis can be initiated by intracellular (intrinsic) or extracellular (extrinsic) stimuli. Intrinsic apoptosis critically relies on mitochondrial outer membrane permeabilization (MOMP), a process that results in the holocytochrome c (CYTC)-, deoxy-ATP- and apoptotic peptidase-activating factor 1 (APAF1)-dependent activation of caspase-9 (CASP9) and CASP3.,,,, MOMP obligatorily requires either of two Bcl-2 family members, namely, B-cell CLL/lymphoma 2 (BCL2)-associated X protein (BAX) and BCL2-antagonist/killer 1 (BAK1), whose pore-forming activity is inhibited (both directly and via indirect circuitries) by other components of the family, including BCL2 itself, BCL2-like 1 (BCL2L1, best known as BCL-XL) and myeloid cell leukemia 1 (MCL1).,,,, Importantly, the physical and functional interactions between pro- and antiapoptotic multidomain BCL2-like proteins are under the control of small components of the family known as BH3-only proteins, including (but not limited to) BCL2 binding component 3 (BBC3, best known as PUMA), BCL2-like 11 (BCL2L11, best known as BIM) and BH3-interacting domain death agonist (BID).,,

17Extrinsic apoptosis proceeds along with the activation of a CASP8/CASP3 signal transduction axis that in some cell types (including hepatocytes, pancreatic β cells and multiple neoplastic cells) also involves MOMP, owing to the CASP8-dependent activation of BID.,,,,, Whether the apoptotic response to extracellular cues requires MOMP or not reportedly depends on the expression levels of X-linked inhibitor of apoptosis (XIAP),, an ubiquitin ligase with multipronged cytoprotective functions., High amounts of XIAP prevent indeed the direct activation of CASP3 by CASP8, a block that can be circumvented by the release of diablo, IAP-binding mitochondrial protein (DIABLO, best known as second mitochondria-derived activator of caspases, SMAC) and other XIAP inhibitors into the cytosol following MOMP.,,,,

18It recently became clear that the main players in the RCD subroutine commonly referred to as necroptosis, which we previously defined as a caspase-independent, RIPK1- and RIPK3-dependent lethal signaling pathway initiated by death receptors,, include not only RIPK1 and RIPK3, as initially thought,,,,,,, but also MLKL.,,,,,,,,,, The kinase activity of RIPK1 is required for necroptosis as induced by multiple stimuli, including death receptor ligation in the presence of caspase inhibitors.,,,,, Conversely, catalytically inactive and Nec-1-bound RIPK1 inhibits the necroptotic response of CASP8-incompetent cells to Toll-like receptor (TLR) agonists or type I interferons, which relies not only on RIPK3 but also on TLR adaptor molecule 1 (TICAM1, best known as TRIF).,,, In the absence of RIPK1, TLR agonists and type I interferons trigger necroptosis even in caspase-competent cells,, suggesting that RIPK1 can inhibit necroptotic RCD as induced by these stimuli at two distinct levels. Furthermore, RIPK1 tonically suppresses CASP8 and RIPK3 activation in developmental scenarios independent of its kinase activity.,, This explains why Ripk1−/− mice fail to survive to adulthood even in the absence of Fas (TNFRSF6)-associated via death domain (Fadd), which is required for CASP8 activation by extracellular cues, but mature normally in the absence of both Ripk3 and Fadd or Casp8. Other instances of necroptosis, such as those promoted by Z-DNA-binding protein 1 (ZBP1) in response to viral infection, appear to proceed independently of RIPK1. Upon phosphorylation by RIPK3, MLKL has a critical, non-redundant role in necroptosis., Phosphorylated MLKL forms indeed oligomers that translocate to cellular membranes (including the plasma membrane) and bind specific phospholipids, resulting in the loss of barrier function.,,,,

19Recent data argue against an essential role for mitochondria in necroptosis. Indeed, parkin RBR E3 ubiquitin protein ligase (PARK2)-overexpressing cells depleted of the vast majority of mitochondria upon the induction of mitophagy (by means of a mitochondrial uncoupler) become resistant to inducers of MOMP-dependent RCD, but remain sensitive to TNFR1 ligation in the presence of Z-VAD-fmk (a conventional trigger of necroptosis). Moreover, contrary to initial beliefs, the lethal activity of RIPK3 is not influenced by the absence of phosphoglycerate mutase family member 5 (PGAM5) and dynamin 1 like (DNM1L, best known as dynamin-related protein 1, DRP1).,, Based on these results, the NCCD proposes here to redefine necroptosis as an RCD modality that critically depends on MLKL and on the kinase activity of RIPK1 (in some settings) and RIPK3. Of note, both RIPK1 and RIPK3 have been shown to regulate caspase activation, at least under some circumstances.,,, Taken together, these observations suggest that the signal transduction cascades responsible for the initiation of apoptosis and necroptosis are highly interconnected.

20Necroptosis is actively inhibited by a supramolecular complex containing CASP8, FADD and the long isoform of CASP8 and FADD-like apoptosis regulator (CFLAR, best known as cellular FLICE inhibitor protein, c-FLIP),,,, three key components of caspase-dependent RCD initiated by death receptors.,,,,, Taken together with the notion that the absence of either Ripk3, Casp8 or Fadd fails to rescue Ripk1−/− mice from neonatal lethality,, these results pointed to the existence of a switch mechanism that regulates cell fate upon TNFR1 ligation., Intriguingly, such switch may not operate in all cell types, as demonstrated by the fact that Ripk1−/− intestinal epithelial cells are fully rescued by the concomitant absence of Casp8 (Peter Vandenabeele, personal communication).

21Recent data obtained with genetically engineered RIPK1 and RIPK3 variants indicate that the catalytic pathways activated in response to death receptor ligation depend on the availability of CASP8, FADD and MLKL. In comparatively more physiologic conditions, however, the fate of cells exposed to death receptor ligands may be determined by the activation kinetics of mitogen-activated protein kinase kinase kinase 7 (MAP3K7, best known as TGFβ-activated kinase 1, TAK1),,, which normally initiates a cytoprotective response centered around the transcription factor NF-κB and autophagy,,,,, or by the availability of baculoviral IAP repeat containing (BIRC) family members,, ubiquitin ligases with a central role in TNFR1 signaling. In line with this notion, cells treated with a SMAC mimetic (resulting in the depletion of BIRC2 and BIRC3) or a chemical TAK1 inhibitor (NP-009245) reportedly respond to TNFR1 ligation by activating caspases in a RIPK1-dependent manner. Taken together, these observations indicate that death receptors generate a lethal stimulus that can be propagated along several signal transduction cascades. Thus, caution should be used in evaluating necroptotic instances of cell death based on their sensitivity to Nec-1 only.

22Another variant of RCD that often, although not always, manifests with a necrotic morphotype critically relies on CYPD. At present, CYPD is the sole genetically confirmed component of the permeability transition pore complex (PTPC) in the mammalian system.,,,,, The term PTPC generally refers to a supramolecular complex operating at the junctions between the inner and outer mitochondrial membrane to cause the so-called ‘mitochondrial permeability transition' (MPT), an abrupt increase in the permeability of the inner mitochondrial membrane to small solutes triggered by cytosolic Ca2+ overload or oxidative stress.,,,, Unlike MOMP,,,, MPT seals the cell fate independently of caspase activation.,, Nonetheless, MPT-driven RCD can manifest with (at least some) morphologic features associated with apoptosis,,, corroborating the limited informative value of cell death classifications solely based on morphology. The NCCD recommends the use of the term ‘MPT-driven RCD' for instances of cell death whose course can be influenced with the genetic or pharmacologic inhibition of CYPD or other components of the PTPC. Of note, CYPD surely does not constitute the long-sought pore-forming unit of the PTPC, which most likely involves subunits of the so-called ‘ATP synthasome', the supramolecular complex that imports ADP and inorganic phosphate into the mitochondrial matrix, catalyzes ATP synthesis and exports ATP back to the mitochondrial intermembrane space (from where it can easily reach the cytosol).,,,,, Perhaps, the central role of CYPD in MPT-driven RCD reflects its ability to control the Ca2+-buffering capacity of the mitochondrial network., This hypothesis has not yet been formally addressed.

23Two forms of RCD other than necroptosis and MPT-driven RCD have recently attracted attention as potential targets for the development of cytoprotective interventions, namely ‘parthanatos' and ‘ferroptosis'. The main molecular features of parthanatos are the hyperactivation of PARP1 and the release of apoptosis-inducing factor, mitochondrion-associated, 1 (AIFM1) from the mitochondria.,,, Interestingly, although TNFR1-driven necroptosis and parthanatos have been suggested to constitute completely independent RCD subroutines, this issue remains a matter of debate., Possibly, such a controversy originates from the ability of some insults to simultaneously trigger necroptosis and parthanatos, at least in some model systems. Ferroptosis has been defined as an iron-dependent form of RCD under the control of glutathione peroxidase 4 (GPX4).,,, Both the pharmacologic and genetic inhibition of CYPD fail to prevent ferroptosis as triggered by erastin, a small molecule that is selectively lethal for cancer cells expressing oncogenic variants of Harvey rat sarcoma viral oncogene homolog (HRAS)., This suggests that ferroptosis and MPT-driven RCD constitute independent variants of RCD. Of note, erastin inhibits system xC−, an heterodimeric antiporter of the plasma membrane that normally exchanges intracellular glutamate for extracellular cysteine, resulting in glutathione depletion and iron-dependent accumulation of reactive oxygen species. A similar cascade of events contributes to (but is not the sole etiological determinant of) the death of neurons exposed to glutamate. This necrotic instance of RCD has previously been referred to as oxytosis., Besides inhibiting system xC−, glutamate can trigger MPT-driven RCD upon the hyperactivation of ionotropic receptors, a neurotoxic process commonly known as excitotoxicity.,

24Caspase-unrelated variants of RCD include ‘autophagic cell death', which (among other processes) is biochemically associated with the lipidation of microtubule-associated protein 1 light chain 3 (MAP1LC3, best known as LC3) and the degradation of sequestosome 1 (SQSTM1, best known as p62). The NCCD recommends using this term only for RCD instances that can be influenced by the pharmacologic or genetic interventions targeting at least two distinct components of the molecular machinery for autophagy., While autophagy accompanies RCD in a vast number of pathophysiologic settings,,, it truly contributes to the cellular demise only in a few of them.,,,,,,,,, Beth Levine's laboratory has recently discovered a bona fide instance of autophagic cell death that relies on the plasma membrane Na+/K+-ATPase, and dubbed it ‘autosis'. Of note, autosis occurs not only in vitro, in cells exposed to cell permeant autophagy-inducing peptides, but also in vivo, in the brain of rats subjected to an ischemic insult. It remains to be determined whether all cases of autophagic cell death require the Na+/K+-ATPase or not. If so, the terms ‘autosis' and ‘autophagic cell death' would be synonymous. If not, autosis would constitute a special instance of autophagic cell death.

25Importantly, a growing body of evidence indicates that the pharmacologic or genetic inhibition of the processes that are commonly considered as essential for cell death execution often does not avoid the demise of mammalian cells, but rather alters its kinetics and biochemical (and morphologic) manifestations. Thus, in many experimental paradigms (in vitro and in vivo), Z-VAD-fmk and more specific CASP3 inhibitors administered as therapeutic (as opposed to prophylactic) interventions fail to significantly limit primary RCD, in spite of the fact that they efficiently limit caspase activation.,,,, In some of these scenarios, RCD overtly manifests with alternative biochemical processes, including RIPK1, RIPK3 or PARP1 activation, and (at least in part) can be influenced by agents that interfere with these pathways, including Nec-1, 3-aminobenzamide (a PARP1-targeting agent) and necrosulfonamide (an inhibitor of human MLKL).,, However, the proportion of cells eventually succumbing to RCD does not change. The depletion of BIRC2/BIRC3, RIPK1, RIPK3 or MLKL, and the administration of NP-009245, Nec-1 or geldanamycin (which indirectly destabilizes RIPK1) reportedly changes the kinetics of necroptosis and its biochemical profile, that is, it allows for caspase activation, yet fails to block the cellular demise.,,,, Along similar lines, 3-aminobenzamide and 4-amino-1,8-naphthalimide (another PARP1 inhibitor) can convert the cytotoxic response to alkylating DNA damage or TNFR1 ligation from a caspase-independent one to apoptosis, manifesting with caspase activation.,,

26These observations indicate that, similar to their morphologic counterparts, the biochemical manifestations of cell death can be altered in the absence of efficient cytoprotection.

RCD and Stress Adaptation

27Cells subjected to perturbations of intracellular or extracellular homeostasis almost invariably mount a tightly coordinated response aimed at (1) the removal of the initiating stimulus (when possible), (2) the repair of molecular and/or organelle damage, and (3) eventually, the re-establishment of physiologic conditions.,,,,,,, When these objectives cannot be attained, cells generally undergo RCD as a means to preserve the homeostasis of the whole organism (or colony, in the case of yeast cells). Two mutually exclusive models can be put forward to explain how adaptive stress responses promote RCD when unsuccessful. First, a ‘conversion model' postulates that RCD-inhibitory signals cease at some stage of the adaptive response and are replaced by RCD-promoting ones. Second, a ‘competition model' hypothesizes that RCD-inhibitory and -promoting signals coexist and counteract with each other starting from the detection of microenvironmental alterations, but at some stage the latter predominate over the former (Figure 2). Although data formally favoring one of these models over the other are lacking, circumstantial evidence suggests that RCD-promoting signals are activated when RCD-inhibitory mechanisms are still operational.,,,,,,,

28Based on this conceptual construction, the NCCD recommends to use the term ‘initiation' to indicate the RCD-causing events that are reversible, that is, that do not irrevocably commit cells to die as they occur when adaptive responses are still operational. In addition, we encourage the use of the expression ‘execution' for referring to the processes that irreversibly and causally seal the cell fate, and the term ‘propagation' to indicate the processes that link primary (stimulus-dependent) RCD to the stimulus-independent initiation of a secondary RCD wave, including the release of DAMPs and the consequent inflammatory response (Figure 3). The blockage of RCD-initiating mechanisms by either pharmacologic or genetic means has been associated with consistent degrees of cytoprotection in rodent models representing various human diseases linked to unwarranted cell death. For instance, this applies to the whole-body ablation of Ppif (the CYPD-coding gene),,,, Ripk3,,,,,, and Mlkl,, as well as to the administration of chemical CYPD inhibitors (i.e., cyclosporin A and sanglifehrin A) and Nec-1., Conversely, pharmacologic and genetic interventions expected to interrupt RCD at late steps of the process (when cells are commonly considered as committed to die) generally fail to confer significant long-term cytoprotection in mammalian models, casting doubts on the actual etiological value of these steps for RCD. Thus, Casp3−/−, Casp9−/− and Apaf1−/− mice display a consistent hyperplasia of the central nervous system associated with reduced amounts of PCD in specific cerebral areas, resulting in embryonic or perinatal lethality.,,,,, However, the neuronal phenotype of Casp3−/− mice does not develop in all genetic backgrounds,,, and the penetrance of the perinatal lethality associated with the Apaf1−/− genotype is incomplete (as some animals survive through 10 months of age)., Moreover, the developmental death of interdigital cells (which generally manifests with biochemical correlates of apoptosis) occurs close to normally (allowing for normal morphogenesis) in mice bearing a homozygous loss-of-function mutation in Apaf1, and in mice exposed to broad-spectrum caspase inhibitors. In these settings, however, the demise of interdigital cells cannot be detected by the terminal-deoxynucleotidyl-mediated dUTP nick end-labeling (TUNEL) assay, measuring caspase-dependent DNA fragmentation. Conversely, the simultaneous ablation of Bax and Bak1 or Bcl2l11 and Bmf (encoding two BH3-only proteins involved in MOMP initiation),, truly prevents the programmed demise of several cell types, causing their persistence throughout adult life., These observations are compatible with the hypothesis that the phenotype associated with some defects in the molecular cascades linking MOMP to caspase activation originates from a delay, rather than from bona fide inhibition, of PCD. Moreover they suggest that RCD, be it programmed or caused by microenvironmental perturbations, can only be avoided by interventions that target upstream steps of the process.

29Caution should also be taken in inferring the actual etiological value of caspases in RCD based on the therapeutic administration of Z-VAD-fmk or other broad-spectrum caspase inhibitors. Caspase blockers have indeed been associated with (at least some degree of) cytoprotection in rodent models of various human diseases linked to the excessive loss of parenchymal cells. These pathologies include, but are not limited to, neurodegenerative disorders,,,,, traumatic events, and ischemia/reperfusion injuries of the central nervous system, heart and kidney.,,, Nonetheless, Z-VAD-fmk and similar compounds inhibit not only several caspases but also a wide panel of non-caspase proteases that participate in the initiation of RCD, such as calpains., Moreover, CASP3, caspase-6 (CASP6) and caspase-7 (CASP7) (i.e., the putative executioners of apoptosis) have been involved in feedforward circuitries that amplify lethal cues leading to MOMP,,,, implying that their inhibition may also counteract the initiation of RCD. Finally, in models of this type it is difficult to discriminate between the primary wave of RCD (promoted by experimental interventions) and the delayed, secondary demise of parenchymal cells caused by DAMPs (directly or upon the establishment of inflammation).,,, The cytoprotective effects that Z-VAD-fmk-like chemicals exert in similar scenarios, which are most reliably evaluated by histological determinations or functional tests, might therefore reflect their ability to block the initiation of DAMP- and inflammation-driven secondary RCD rather than the execution of stimulus-induced, primary RCD. In line with this notion, consistent cytoprotection has also been achieved in vivo by means of anti-inflammatory agents, even when these compounds do not directly influence RCD.,,, Taken together, these observations reinforce the notion that caspases may not mediate RCD but simply accelerate its course, at least in the mammalian system.

30Apparently at odds with the role of PARP1 in the execution of parthanatos, both the Parp1−/− genotype and the administration of (relatively unselective) PARP inhibitors have been associated with bona fide cytoprotection in rodent models of ischemia/reperfusion injury and retinal degeneration.,,, These observations suggest that PARP1 and/or other members of the PARP family also participate in the initiation of RCD. Alternatively, the inhibition of PARP1 may limit the release of DAMPs or the consequent inflammatory response, at least in some pathophysiologic settings. Further experiments are required to clarify these possibilities.

Concluding Remarks

31As discussed above, the processes that until now were thought to mediate RCD most often do not causally underpin the cellular demise but represent biochemical manifestations of it. A growing body of data indicates indeed that the bona fide executioners of RCD, that is, the processes that directly drive cells across the boundary between life and death are less characterized, less inhibitable and perhaps more homogeneous than previously thought. In line with this theoretical construction, here the NCDD proposes to use the term ‘initiation' to refer to all the steps in the RCD cascade that are reversible, that is, which occur before cells make an irrevocable commitment to die. An attentive reinterpretation of the literature suggests that actual cytoprotection can only be achieved with pharmacologic or genetic interventions that inhibit or outcompete lethal signals at this stage, when adaptive responses to stress are still operational. Interestingly, some cells manifesting biochemical and morphologic features associated with late-stage RCD (including partial MOMP, caspase activation and blebbing) appear to recover (upon removal of the RCD-initiating insult) and replicate, a process that has been dubbed ‘anastasis' (from the ancient Greek ‘ανστασις', meaning ‘raising to life')., This suggests that the actual point of no return in the signal-transduction cascades leading to RCD may exhibit at least some degree of context dependency.

32In the vast majority of scientific reports, RCD is measured in vitro 24–96 h after stimulation, whereas the most reliable assessment of RCD in vivo is based upon histologic determinations or functional tests performed days, if not weeks or months, after such experimental interventions. In the former scenario, investigators can collect valuable kinetic data but are unable to estimate the true long-term survival of cells exposed to perturbations of homeostasis. In the second scenario, it is difficult to discriminate between the interruption of primary RCD and the inhibition of DAMP-driven inflammatory reactions and secondary RCD. This may have profound mechanistic and therapeutic implications. Indeed, retarding the demise of a cell that has already committed to die in an irreversible manner, and the biochemical manifestations of such death, may have limited cytoprotective effects for the cell in question, but may impact on the emission of DAMPs and hence significantly influence RCD propagation. Thus, considerable degrees of cytoprotection might be attained by means of agents that interrupt lethal cues at (or before) RCD initiation (when adaptive stress responses are still functional) combined with strategies that inhibit propagation (e.g., chemicals that favor RCD instances associated with a limited release of DAMPs, DAMP-neutralizing measures, anti-inflammatory agents). The superior beneficial effects of cyclosporin A may indeed stem from its ability to inhibit MPT-driven RCD and simultaneously exert a robust anti-inflammatory activity.,

33If caspases and other enzymes commonly thought to mediate RCD in mammalian cells only underpin its manifestations, what are the true causes of cell death? Although the concentration of ATP is preserved (or even increases to some extent) in the course of adaptive stress responses,, circumstantial evidence points to dropping ATP levels, which at some point abolish the activity of all ATP-dependent enzymes (including various transporters that maintain ionic balance at the plasma membrane) and a compromised redox balance (which inactivates various enzymes and causes oxidative molecular damage to organelles and membranes) as central players in the execution of RCD (Figure 4). Alternatively, one or more hitherto uncharacterized mechanism(s) may causally underpin RCD in all its manifestations. Further experiments are required to explore these possibilities.

34At odds with mammalian models, Caenorhabditis elegans and D. melanogaster are truly protected by Z-VAD-fmk and by the genetic inhibition of caspase orthologs and other proteins involved in the postmitochondrial phase of apoptosis.,,,,,, This may indicate that the signal transduction cascades underlying RCD are interconnected in a different manner in mammals and non-mammalian organisms. Alternatively, the actual requirement of caspases for (at least some instances of) RCD might have been concealed by the evolutionary expansion of the caspase family. Both the human and murine genome encode indeed 14 distinct caspases,, and it seems unlikely that Z-VAD-fmk and other pharmacologic or genetic interventions may simultaneously inhibit all of them in an efficient manner.

35Until these uncertainties have been resolved, the NCCD recommends that investigators focus on essential aspects of cell death; first of all its actual occurrence. It appears indeed that measuring the functional status or subcellular localization of RCD-relevant proteins including (but not limited to) caspases, RIPK1, RIPK3, MLKL, CYPD, PARP1 and GPX4, can provide insights into the mechanisms that accompany (and regulate the kinetics of) cellular demise, but not into those that truly push cells beyond the point-of-no-return separating life and death. Precisely defining where this border stands from a bioenergetic and metabolic perspective may facilitate the development of novel and efficient cytoprotective agents for clinical use.

References 337

1.
Mazzarello P A unifying concept: the history of cell theoryNat Cell Biol1999 1E13E15
Not in our library10.1038/8964
2.
Cotter TG Apoptosis and cancer: the genesis of a research fieldNat Rev Cancer2009 9501507
Not in our library10.1038/nrc2663
3.
Schweichel JU Merker HJ The morphology of various types of cell death in prenatal tissuesTeratology1973 7253266
Not in our library10.1002/tera.1420070306
4.
Vaux DL Apoptosis timelineCell Death Differ2002 9349354
Not in our library10.1038/sj.cdd.4400990
5.
Pearson H ‘Virophage' suggests viruses are aliveNature2008 454677
Not in our library10.1038/454677a
6.
La Scola B Audic S Robert C Jungang L de Lamballerie X Drancourt M A giant virus in amoebaeScience2003 2992033
Not in our library10.1126/science.1081867
7.
La Scola B Desnues C Pagnier I Robert C Barrassi L Fournous G The virophage as a unique parasite of the giant mimivirusNature2008 455100104
Not in our library10.1038/nature07218
8.
Raoult D Forterre P Redefining viruses: lessons from MimivirusNat Rev Microbiol2008 6315319
Not in our library10.1038/nrmicro1858
9.
Galluzzi L Vitale I Abrams JM Alnemri ES Baehrecke EH Blagosklonny MV Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell DeathCell Death Differ2012 19107120
Not in our library10.1038/cdd.2011.96
10.
Kroemer G Galluzzi L Vandenabeele P Abrams J Alnemri ES Baehrecke EH Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009Cell Death Differ2009 16311
Not in our library10.1038/cdd.2008.150
11.
Galluzzi L Maiuri MC Vitale I Zischka H Castedo M Zitvogel L Cell death modalities: classification and pathophysiological implicationsCell Death Differ2007 1412371243
Not in our library10.1038/sj.cdd.4402148
12.
Poon IK Lucas CD Rossi AG Ravichandran KS Apoptotic cell clearance: basic biology and therapeutic potentialNat Rev Immunol2014 14166180
Not in our library10.1038/nri3607
13.
Hochreiter-Hufford A Ravichandran KS Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestionCold Spring Harb Perspect Biol2013 5a008748
Not in our library10.1101/cshperspect.a008748
14.
Underhill DM Goodridge HS Information processing during phagocytosisNat Rev Immunol2012 12492502
Not in our library10.1038/nri3244
15.
Overholtzer M Mailleux AA Mouneimne G Normand G Schnitt SJ King RW A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasionCell2007 131966979
Not in our library10.1016/j.cell.2007.10.040
16.
Galluzzi L Kepp O Kroemer G Mitochondria: master regulators of danger signallingNat Rev Mol Cell Biol2012 13780788
Not in our library10.1038/nrm3479
17.
Klionsky DJ Abdalla FC Abeliovich H Abraham RT Acevedo-Arozena A Adeli K Guidelines for the use and interpretation of assays for monitoring autophagyAutophagy2012 8445544
Not in our library10.4161/auto.19496
18.
Kepp O Galluzzi L Lipinski M Yuan J Kroemer G Cell death assays for drug discoveryNat Rev Drug Discov2011 10221237
Not in our library10.1038/nrd3373
19.
Zhang Q Raoof M Chen Y Sumi Y Sursal T Junger W Circulating mitochondrial DAMPs cause inflammatory responses to injuryNature2010 464104107
Not in our library10.1038/nature08780
20.
Galluzzi L Aaronson SA Abrams J Alnemri ES Andrews DW Baehrecke EH Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotesCell Death Differ2009 1610931107
Not in our library10.1038/cdd.2009.44
21.
Tasdemir E Galluzzi L Maiuri MC Criollo A Vitale I Hangen E Methods for assessing autophagy and autophagic cell deathMethods Mol Biol2008 4452976
Not in our library10.1007/978-1-59745-157-4_3
22.
Krysko DV Vanden Berghe T D'Herde K Vandenabeele P Apoptosis and necrosis: detection, discrimination and phagocytosisMethods2008 44205221
Not in our library10.1016/j.ymeth.2007.12.001
23.
Green DR Kroemer G Pharmacological manipulation of cell death: clinical applications in sightJ Clin Invest2005 11526102617
Not in our library10.1172/jci26321
24.
Vanden Berghe T Grootjans S Goossens V Dondelinger Y Krysko DV Takahashi N Determination of apoptotic and necrotic cell death in vitro and in vivoMethods2013 61117129
Not in our library10.1016/j.ymeth.2013.02.011
25.
Grootjans S Goossens V Vandenabeele P Vanden Berghe T Methods to study and distinguish necroptosisCell Death in Biology and Diseases: Necrotic Cell DeathHumana Press, SpringerNew York, NY, USA2014 335361
Not in our library
26.
Long JS Ryan KM New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagyOncogene2012 3150455060
Not in our library10.1038/onc.2012.7
27.
MacFarlane M Cell death pathways – potential therapeutic targetsXenobiotica2009 39616624
Not in our library10.1080/00498250903137990
28.
Reed JC Drug insight: cancer therapy strategies based on restoration of endogenous cell death mechanismsNat Clin Pract Oncol2006 3388398
Not in our library10.1038/ncponc0538
29.
Brenner C Galluzzi L Kepp O Kroemer G Decoding cell death signals in liver inflammationJ Hepatol2013 59583594
Not in our library10.1016/j.jhep.2013.03.033
30.
Zelenay S Reis e Sousa C Adaptive immunity after cell deathTrends Immunol2013 34329335
Not in our library10.1016/j.it.2013.03.005
31.
Sims GP Rowe DC Rietdijk ST Herbst R Coyle AJ HMGB1 and RAGE in inflammation and cancerAnnu Rev Immunol2010 28367388
Not in our library10.1146/annurev.immunol.021908.132603
32.
Zitvogel L Kepp O Kroemer G Decoding cell death signals in inflammation and immunityCell2010 140798804
Not in our library10.1016/j.cell.2010.02.015
33.
Galluzzi L Kepp O Krautwald S Kroemer G Linkermann A Molecular mechanisms of regulated necrosisSemin Cell Dev Biol2014
Not in our library10.1016/j.semcdb.2014.02.006
34.
Bhattacharyya S Yu H Mim C Matouschek A Regulated protein turnover: snapshots of the proteasome in actionNat Rev Mol Cell Biol2014 15122133
Not in our library10.1038/nrm3741
35.
Cellular Stress Responses: Cell Survival and Cell Death · 2010
No notice
36.
Kroemer G Marino G Levine B Autophagy and the integrated stress responseMol Cell2010 40280293
Not in our library10.1016/j.molcel.2010.09.023
37.
Richter K Haslbeck M Buchner J The heat shock response: life on the verge of deathMol Cell2010 40253266
Not in our library10.1016/j.molcel.2010.10.006
38.
Spriggs KA Bushell M Willis AE Translational regulation of gene expression during conditions of cell stressMol Cell2010 40228237
Not in our library10.1016/j.molcel.2010.09.028
39.
Haynes CM Fiorese CJ Lin YF Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-protein response and beyondTrends Cell Biol2013 23311318
Not in our library10.1016/j.tcb.2013.02.002
40.
Choi AM Ryter SW Levine B Autophagy in human health and diseaseN Engl J Med2013 368651662
Not in our library10.1056/nejmra1205406
41.
Jensen MB Jasper H Mitochondrial proteostasis in the control of aging and longevityCell Metab2014 20214225
Not in our library10.1016/j.cmet.2014.05.006
42.
Galluzzi L Bravo-San Pedro JM Kroemer G Organelle-specific initiation of cell deathNat Cell Biol2014 16728736
Not in our library10.1038/ncb3005
43.
Mizushima N Levine B Cuervo AM Klionsky DJ Autophagy fights disease through cellular self-digestionNature2008 45110691075
Not in our library10.1038/nature06639
44.
Amelio I Melino G Knight RA Cell death pathology: cross-talk with autophagy and its clinical implicationsBiochem Biophys Res Commun2011 414277281
Not in our library10.1016/j.bbrc.2011.09.080
45.
Czabotar PE Lessene G Strasser A Adams JM Control of apoptosis by the BCL-2 protein family: implications for physiology and therapyNat Rev Mol Cell Biol2014 154963
Not in our library10.1038/nrm3722
46.
Gogvadze V Orrenius S Zhivotovsky B Mitochondria as targets for cancer chemotherapySemin Cancer Biol2009 195766
Not in our library10.1016/j.semcancer.2008.11.007
47.
Lindner AU Concannon CG Boukes GJ Cannon MD Llambi F Ryan D Systems analysis of BCL2 protein family interactions establishes a model to predict responses to chemotherapyCancer Res2013 73519528
Not in our library10.1158/0008-5472.can-12-2269
48.
Chipuk JE Moldoveanu T Llambi F Parsons MJ Green DR The BCL-2 family reunionMol Cell2010 37299310
Not in our library10.1016/j.molcel.2010.01.025
49.
Rubinsztein DC Codogno P Levine B Autophagy modulation as a potential therapeutic target for diverse diseasesNat Rev Drug Discov2012 11709730
Not in our library10.1038/nrd3802
50.
White E Deconvoluting the context-dependent role for autophagy in cancerNat Rev Cancer2012 12401410
Not in our library10.1038/nrc3262
51.
Taylor RC Cullen SP Martin SJ Apoptosis: controlled demolition at the cellular levelNat Rev Mol Cell Biol2008 9231241
Not in our library10.1038/nrm2312
52.
Lettre G Hengartner MO Developmental apoptosis in C. elegans: a complex CEDnarioNat Rev Mol Cell Biol2006 797108
Not in our library10.1038/nrm1836
53.
Fuchs Y Steller H Programmed cell death in animal development and diseaseCell2011 147742758
Not in our library10.1016/j.cell.2011.10.033
54.
Delbridge AR Valente LJ Strasser A The role of the apoptotic machinery in tumor suppressionCold Spring Harb Perspect Biol2012 4
Not in our library10.1101/cshperspect.a008789
55.
Strasser A Jost PJ Nagata S The many roles of FAS receptor signaling in the immune systemImmunity2009 30180192
Not in our library10.1016/j.immuni.2009.01.001
56.
Peter ME Budd RC Desbarats J Hedrick SM Hueber AO Newell MK The CD95 receptor: apoptosis revisitedCell2007 129447450
Not in our library10.1016/j.cell.2007.04.031
57.
Walczak H Death receptor-ligand systems in cancer, cell death, and inflammationCold Spring Harb Perspect Biol2013 5a008698
Not in our library10.1101/cshperspect.a008698
58.
Lockshin RA Williams CM Programmed cell death II. Endocrine potentiation of the breakdown of the intersegmental muscles of silkmothsJ Insect Phys1964 10643649
Not in our library
59.
Apoptosis: A Basic Biological Phenomenon with Wideranging Implications in Tissue Kinetics · 1972
No notice
60.
Clarke PG Developmental cell death: morphological diversity and multiple mechanismsAnat Embryol (Berl)1990 181195213
Not in our library10.1007/bf00174615
61.
Igney FH Krammer PH Death and anti-death: tumour resistance to apoptosisNat Rev Cancer2002 2277288
Not in our library10.1038/nrc776
62.
Bellamy CO Malcomson RD Harrison DJ Wyllie AH Cell death in health and disease: the biology and regulation of apoptosisSemin Cancer Biol1995 6316
Not in our library10.1006/scbi.1995.0002
63.
Tracy K Baehrecke EH The role of autophagy in Drosophila metamorphosisCurr Top Dev Biol2013 103101125
Not in our library10.1016/b978-0-12-385979-2.00004-6
64.
Nezis IP Shravage BV Sagona AP Lamark T Bjorkoy G Johansen T Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesisJ Cell Biol2010 190523531
Not in our library10.1083/jcb.201002035
65.
Denton D Shravage B Simin R Baehrecke EH Kumar S Larval midgut destruction in Drosophila: not dependent on caspases but suppressed by the loss of autophagyAutophagy2010 6163165
Not in our library10.4161/auto.6.1.10601
66.
Denton D Shravage B Simin R Mills K Berry DL Baehrecke EH Autophagy, not apoptosis, is essential for midgut cell death in DrosophilaCurr Biol2009 1917411746
Not in our library10.1016/j.cub.2009.08.042
67.
Berry DL Baehrecke EH Growth arrest and autophagy are required for salivary gland cell degradation in DrosophilaCell2007 13111371148
Not in our library10.1016/j.cell.2007.10.048
68.
Baehrecke EH Autophagy: dual roles in life and deathNat Rev Mol Cell Biol2005 6505510
Not in our library10.1038/nrm1666
69.
Denton D Aung-Htut MT Lorensuhewa N Nicolson S Zhu W Mills K UTX coordinates steroid hormone-mediated autophagy and cell deathNat Commun2013 42916
Not in our library10.1038/ncomms3916
70.
Denton D Chang TK Nicolson S Shravage B Simin R Baehrecke EH Relationship between growth arrest and autophagy in midgut programmed cell death in DrosophilaCell Death Differ2012 1912991307
Not in our library10.1038/cdd.2012.43
71.
Roach HI Clarke NM Physiological cell death of chondrocytes in vivo is not confined to apoptosis. New observations on the mammalian growth plateJ Bone Joint Surg Br2000 82601613
Not in our library10.1302/0301-620x.82b4.9846
72.
Kroemer G Galluzzi L Kepp O Zitvogel L Immunogenic cell death in cancer therapyAnnu Rev Immunol2013 315172
Not in our library10.1146/annurev-immunol-032712-100008
73.
Krysko DV Garg AD Kaczmarek A Krysko O Agostinis P Vandenabeele P Immunogenic cell death and DAMPs in cancer therapyNat Rev Cancer2012 12860875
Not in our library10.1038/nrc3380
74.
Vandenabeele P Galluzzi L Vanden Berghe T Kroemer G Molecular mechanisms of necroptosis: an ordered cellular explosionNat Rev Mol Cell Biol2010 11700714
Not in our library10.1038/nrm2970
75.
Kroemer G Levine B Autophagic cell death: the story of a misnomerNat Rev Mol Cell Biol2008 910041010
Not in our library10.1038/nrm2527
76.
Denton D Nicolson S Kumar S Cell death by autophagy: facts and apparent artefactsCell Death Differ2012 198795
Not in our library10.1038/cdd.2011.146
77.
Martinou I Desagher S Eskes R Antonsson B Andre E Fakan S The release of cytochrome c from mitochondria during apoptosis of NGF-deprived sympathetic neurons is a reversible eventJ Cell Biol1999 144883889
Not in our library10.1083/jcb.144.5.883
78.
Vandenabeele P Vanden Berghe T Festjens N Caspase inhibitors promote alternative cell death pathwaysSci STKE2006 2006pe44
Not in our library10.1126/stke.3582006pe44
79.
Scheller C Knoferle J Ullrich A Prottengeier J Racek T Sopper S Caspase inhibition in apoptotic T cells triggers necrotic cell death depending on the cell type and the proapoptotic stimulusJ Cell Biochem2006 9713501361
Not in our library10.1002/jcb.20670
80.
Chautan M Chazal G Cecconi F Gruss P Golstein P Interdigital cell death can occur through a necrotic and caspase-independent pathwayCurr Biol1999 9967970
Not in our library10.1016/s0960-9822(99)80425-4
81.
Hirsch T Marchetti P Susin SA Dallaporta B Zamzami N Marzo I The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell deathOncogene1997 1515731581
Not in our library10.1038/sj.onc.1201324
82.
Lockshin RA Zakeri Z Caspase-independent cell deathsCurr Opin Cell Biol2002 14727733
Not in our library10.1016/s0955-0674(02)00383-6
83.
Mailleux AA Overholtzer M Schmelzle T Bouillet P Strasser A Brugge JS BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanismsDev Cell2007 12221234
Not in our library10.1016/j.devcel.2006.12.003
84.
Rashmi R Pillai SG Vijayalingam S Ryerse J Chinnadurai G BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cellsOncogene2008 2713661375
Not in our library10.1038/sj.onc.1210783
85.
Okada M Adachi S Imai T Watanabe K Toyokuni SY Ueno M A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activityBlood2004 10322992307
Not in our library10.1182/blood-2003-05-1605
86.
Volbracht C Leist M Kolb SA Nicotera P Apoptosis in caspase-inhibited neuronsMol Med2001 73648
Not in our library
87.
Miyazaki K Yoshida H Sasaki M Hara H Kimura G Mak TW Caspase-independent cell death and mitochondrial disruptions observed in the Apaf1-deficient cellsJ Biochem2001 129963969
Not in our library10.1093/oxfordjournals.jbchem.a002944
88.
Nagasaka A Kawane K Yoshida H Nagata S Apaf-1-independent programmed cell death in mouse developmentCell Death Differ2010 17931941
Not in our library10.1038/cdd.2009.186
89.
Oppenheim RW Flavell RA Vinsant S Prevette D Kuan CY Rakic P Programmed cell death of developing mammalian neurons after genetic deletion of caspasesJ Neurosci2001 2147524760
Not in our library10.1523/jneurosci.21-13-04752.2001
90.
Susin SA Daugas E Ravagnan L Samejima K Zamzami N Loeffler M Two distinct pathways leading to nuclear apoptosisJ Exp Med2000 192571580
Not in our library10.1084/jem.192.4.571
91.
Golstein P Kroemer G Redundant cell death mechanisms as relics and backupsCell Death Differ2005 12(Suppl 214901496
Not in our library10.1038/sj.cdd.4401607
92.
Caserta TM Smith AN Gultice AD Reedy MA Brown TL Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic propertiesApoptosis2003 8345352
Not in our library10.1023/a:1024116916932
93.
Zhu H Fearnhead HO Cohen GM An ICE-like protease is a common mediator of apoptosis induced by diverse stimuli in human monocytic THP.1 cellsFEBS Lett1995 374303308
Not in our library10.1016/0014-5793(95)01116-v
94.
Chow SC Weis M Kass GE Holmstrom TH Eriksson JE Orrenius S Involvement of multiple proteases during Fas-mediated apoptosis in T lymphocytesFEBS Lett1995 364134138
Not in our library10.1016/0014-5793(95)00370-o
95.
Slee EA Zhu H Chow SC MacFarlane M Nicholson DW Cohen GM Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK) inhibits apoptosis by blocking the processing of CPP32Biochem J1996 315(Part 12124
Not in our library10.1042/bj3150021
96.
Janicke RU Sprengart ML Wati MR Porter AG Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosisJ Biol Chem1998 27393579360
Not in our library10.1074/jbc.273.16.9357
97.
Coleman ML Sahai EA Yeo M Bosch M Dewar A Olson MF Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK INat Cell Biol2001 3339345
Not in our library10.1038/35070009
98.
Enzenmuller S Gonzalez P Karpel-Massler G Debatin KM Fulda S GDC-0941 enhances the lysosomal compartment via TFEB and primes glioblastoma cells to lysosomal membrane permeabilization and cell deathCancer Lett2013 3292736
Not in our library10.1016/j.canlet.2012.09.007
99.
Mediavilla-Varela M Pacheco FJ Almaguel F Perez J Sahakian E Daniels TR Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75Mol Cancer2009 868
Not in our library10.1186/1476-4598-8-68
100.
Rebbaa A Zheng X Chou PM Mirkin BL Caspase inhibition switches doxorubicin-induced apoptosis to senescenceOncogene2003 2228052811
Not in our library10.1038/sj.onc.1206366
101.
Jouan-Lanhouet S Arshad MI Piquet-Pellorce C Martin-Chouly C Le Moigne-Muller G Van Herreweghe F TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activationCell Death Differ2012 1920032014
Not in our library10.1038/cdd.2012.90
102.
Vanden Berghe T Kalai M van Loo G Declercq W Vandenabeele P Disruption of HSP90 function reverts tumor necrosis factor-induced necrosis to apoptosisJ Biol Chem2003 27856225629
Not in our library10.1074/jbc.m208925200
103.
Vanlangenakker N Bertrand MJ Bogaert P Vandenabeele P Vanden Berghe T TNF-induced necroptosis in L929 cells is tightly regulated by multiple TNFR1 complex I and II membersCell Death Dis2011 2e230
Not in our library10.1038/cddis.2011.111
104.
Remijsen Q Goossens V Grootjans S Van den Haute C Vanlangenakker N Dondelinger Y Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosisCell Death Dis2014 5e1004
Not in our library10.1038/cddis.2013.531
105.
Kehe K Raithel K Kreppel H Jochum M Worek F Thiermann H Inhibition of poly(ADP-ribose) polymerase (PARP) influences the mode of sulfur mustard (SM)-induced cell death in HaCaT cellsArch Toxicol2008 82461470
Not in our library10.1007/s00204-007-0265-7
106.
Pogrebniak A Schemainda I Pelka-Fleischer R Nussler V Hasmann M Poly ADP-ribose polymerase (PARP) inhibitors transiently protect leukemia cells from alkylating agent induced cell death by three different effectsEur J Med Res2003 8438450
Not in our library
107.
Los M Mozoluk M Ferrari D Stepczynska A Stroh C Renz A Activation and caspase-mediated inhibition of PARP: a molecular switch between fibroblast necrosis and apoptosis in death receptor signalingMol Biol Cell2002 13978988
Not in our library10.1091/mbc.01-05-0272
108.
Gibson BA Kraus WL New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPsNat Rev Mol Cell Biol2012 13411424
Not in our library10.1038/nrm3376
109.
Michels J Vitale I Saparbaev M Castedo M Kroemer G Predictive biomarkers for cancer therapy with PARP inhibitorsOncogene2013 3338943907
Not in our library10.1038/onc.2013.352
110.
Ankarcrona M Dypbukt JM Bonfoco E Zhivotovsky B Orrenius S Lipton SA Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial functionNeuron1995 15961973
Not in our library10.1016/0896-6273(95)90186-8
111.
Leist M Single B Castoldi AF Kuhnle S Nicotera P Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosisJ Exp Med1997 18514811486
Not in our library10.1084/jem.185.8.1481
112.
Nicotera P Leist M Ferrando-May E Intracellular ATP, a switch in the decision between apoptosis and necrosisToxicol Lett1998 102-103139142
Not in our library10.1016/s0378-4274(98)00298-7
113.
Volbracht C Leist M Nicotera P ATP controls neuronal apoptosis triggered by microtubule breakdown or potassium deprivationMol Med1999 5477489
Not in our library
114.
Eguchi Y Shimizu S Tsujimoto Y Intracellular ATP levels determine cell death fate by apoptosis or necrosisCancer Res1997 5718351840
Not in our library
115.
Nicotera P Melino G Regulation of the apoptosis-necrosis switchOncogene2004 2327572765
Not in our library10.1038/sj.onc.1207559
116.
Saikumar P Differential energy requirements for caspase activation and apoptosisFASEB J2007 21A258
Not in our library
117.
Liu X Kim CN Yang J Jemmerson R Wang X Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome cCell1996 86147157
Not in our library10.1016/s0092-8674(00)80085-9
118.
Chandra D Bratton SB Person MD Tian Y Martin AG Ayres M Intracellular nucleotides act as critical prosurvival factors by binding to cytochrome C and inhibiting apoptosomeCell2006 12513331346
Not in our library10.1016/j.cell.2006.05.026
119.
Bratton SB Salvesen GS Regulation of the Apaf-1-caspase-9 apoptosomeJ Cell Sci2010 12332093214
Not in our library10.1242/jcs.073643
120.
Linkermann A Green DR NecroptosisN Engl J Med2014 370455465
Not in our library10.1056/nejmra1310050
121.
Vanden Berghe T Linkermann A Jouan-Lanhouet S Walczak H Vandenabeele P Regulated necrosis: the expanding network of non-apoptotic cell death pathwaysNat Rev Mol Cell Biol2014 15135147
Not in our library10.1038/nrm3737
122.
Laster SM Wood JG Gooding LR Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysisJ Immunol1988 14126292634
Not in our library
123.
Denecker G Vercammen D Steemans M Vanden Berghe T Brouckaert G Van Loo G Death receptor-induced apoptotic and necrotic cell death: differential role of caspases and mitochondriaCell Death Differ2001 8829840
Not in our library10.1038/sj.cdd.4400883
124.
Vercammen D Brouckaert G Denecker G Van de Craen M Declercq W Fiers W Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathwaysJ Exp Med1998 188919930
Not in our library10.1084/jem.188.5.919
125.
Vercammen D Beyaert R Denecker G Goossens V Van Loo G Declercq W Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factorJ Exp Med1998 18714771485
Not in our library10.1084/jem.187.9.1477
126.
Vercammen D Vandenabeele P Beyaert R Declercq W Fiers W Tumour necrosis factor-induced necrosis versus anti-Fas-induced apoptosis in L929 cellsCytokine1997 9801808
Not in our library10.1006/cyto.1997.0252
127.
Fiers W Beyaert R Boone E Cornelis S Declercq W Decoster E TNF-induced intracellular signaling leading to gene induction or to cytotoxicity by necrosis or by apoptosisJ Inflamm1995 476775
Not in our library
128.
Holler N Zaru R Micheau O Thome M Attinger A Valitutti S Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector moleculeNat Immunol2000 1489495
Not in our library10.1038/82732
129.
Hitomi J Christofferson DE Ng A Yao J Degterev A Xavier RJ Identification of a molecular signaling network that regulates a cellular necrotic cell death pathwayCell2008 13513111323
Not in our library10.1016/j.cell.2008.10.044
130.
Degterev A Hitomi J Germscheid M Ch'en IL Korkina O Teng X Identification of RIP1 kinase as a specific cellular target of necrostatinsNat Chem Biol2008 4313321
Not in our library10.1038/nchembio.83
131.
Degterev A Huang Z Boyce M Li Y Jagtap P Mizushima N Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injuryNat Chem Biol2005 1112119
Not in our library10.1038/nchembio711
132.
Schinzel AC Takeuchi O Huang Z Fisher JK Zhou Z Rubens J Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemiaProc Natl Acad Sci USA2005 1021200512010
Not in our library10.1073/pnas.0505294102
133.
Baines CP Kaiser RA Purcell NH Blair NS Osinska H Hambleton MA Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell deathNature2005 434658662
Not in our library10.1038/nature03434
134.
Nakagawa T Shimizu S Watanabe T Yamaguchi O Otsu K Yamagata H Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell deathNature2005 434652658
Not in our library10.1038/nature03317
135.
Basso E Fante L Fowlkes J Petronilli V Forte MA Bernardi P Properties of the permeability transition pore in mitochondria devoid of cyclophilin DJ Biol Chem2005 2801855818561
Not in our library10.1074/jbc.c500089200
136.
Mellen MA de la Rosa EJ Boya P Autophagy is not universally required for phosphatidyl-serine exposure and apoptotic cell engulfment during neural developmentAutophagy2009 5964972
Not in our library10.4161/auto.5.7.9292
137.
Mellen MA de la Rosa EJ Boya P The autophagic machinery is necessary for removal of cell corpses from the developing retinal neuroepitheliumCell Death Differ2008 1512791290
Not in our library10.1038/cdd.2008.40
138.
Segawa K Kurata S Yanagihashi Y Brummelkamp TR Matsuda F Nagata S Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposureScience2014 34411641168
Not in our library10.1126/science.1252809
139.
Kenis H Zandbergen HR Hofstra L Petrov AD Dumont EA Blankenberg FD Annexin A5 uptake in ischemic myocardium: demonstration of reversible phosphatidylserine externalization and feasibility of radionuclide imagingJ Nucl Med2010 51259267
Not in our library10.2967/jnumed.109.068429
140.
Martin SJ Reutelingsperger CP McGahon AJ Rader JA van Schie RC LaFace DM Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and AblJ Exp Med1995 18215451556
Not in our library10.1084/jem.182.5.1545
141.
Yang J Liu X Bhalla K Kim CN Ibrado AM Cai J Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blockedScience1997 27511291132
Not in our library10.1126/science.275.5303.1129
142.
Li P Nijhawan D Budihardjo I Srinivasula SM Ahmad M Alnemri ES Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascadeCell1997 91479489
Not in our library10.1016/s0092-8674(00)80434-1
143.
Zou H Henzel WJ Liu X Lutschg A Wang X Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3Cell1997 90405413
Not in our library10.1016/s0092-8674(00)80501-2
144.
Ow YP Green DR Hao Z Mak TW Cytochrome c: functions beyond respirationNat Rev Mol Cell Biol2008 9532542
Not in our library10.1038/nrm2434
145.
Hardwick JM Chen YB Jonas EA Multipolar functions of BCL-2 proteins link energetics to apoptosisTrends Cell Biol2012 22318328
Not in our library10.1016/j.tcb.2012.03.005
146.
Danial NN BCL-2 family proteins: critical checkpoints of apoptotic cell deathClin Cancer Res2007 1372547263
Not in our library10.1158/1078-0432.ccr-07-1598
147.
Rong Y Distelhorst CW Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosisAnnu Rev Physiol2008 707391
Not in our library10.1146/annurev.physiol.70.021507.105852
148.
Chipuk JE Green DR How do BCL-2 proteins induce mitochondrial outer membrane permeabilizationTrends Cell Biol2008 18157164
Not in our library10.1016/j.tcb.2008.01.007
149.
Kim H Tu HC Ren D Takeuchi O Jeffers JR Zambetti GP Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosisMol Cell2009 36487499
Not in our library10.1016/j.molcel.2009.09.030
150.
Willis SN Fletcher JI Kaufmann T van Delft MF Chen L Czabotar PE Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or BakScience2007 315856859
Not in our library10.1126/science.1133289
151.
Ren D Tu HC Kim H Wang GX Bean GR Takeuchi O BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death programScience2010 33013901393
Not in our library10.1126/science.1190217
152.
Luo X Budihardjo I Zou H Slaughter C Wang X Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptorsCell1998 94481490
Not in our library10.1016/s0092-8674(00)81589-5
153.
Gross A Yin XM Wang K Wei MC Jockel J Milliman C Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas deathJ Biol Chem1999 27411561163
Not in our library10.1074/jbc.274.2.1156
154.
Yin XM Wang K Gross A Zhao Y Zinkel S Klocke B Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosisNature1999 400886891
Not in our library10.1038/23730
155.
Scaffidi C Schmitz I Zha J Korsmeyer SJ Krammer PH Peter ME Differential modulation of apoptosis sensitivity in CD95 type I and type II cellsJ Biol Chem1999 2742253222538
Not in our library10.1074/jbc.274.32.22532
156.
Gonzalvez F Schug ZT Houtkooper RH MacKenzie ED Brooks DG Wanders RJ Cardiolipin provides an essential activating platform for caspase-8 on mitochondriaJ Cell Biol2008 183681696
Not in our library10.1083/jcb.200803129
157.
Zaltsman Y Shachnai L Yivgi-Ohana N Schwarz M Maryanovich M Houtkooper RH MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondriaNat Cell Biol2010 12553562
Not in our library10.1038/ncb2057
158.
Jost PJ Grabow S Gray D McKenzie MD Nachbur U Huang DC XIAP discriminates between type I and type II FAS-induced apoptosisNature2009 46010351039
Not in our library10.1038/nature08229
159.
Albeck JG Burke JM Aldridge BB Zhang M Lauffenburger DA Sorger PK Quantitative analysis of pathways controlling extrinsic apoptosis in single cellsMol Cell2008 301125
Not in our library10.1016/j.molcel.2008.02.012
160.
Schile AJ Garcia-Fernandez M Steller H Regulation of apoptosis by XIAP ubiquitin-ligase activityGenes Dev2008 2222562266
Not in our library10.1101/gad.1663108
161.
Srinivasula SM Hegde R Saleh A Datta P Shiozaki E Chai J A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosisNature2001 410112116
Not in our library10.1038/35065125
162.
Verhagen AM Ekert PG Pakusch M Silke J Connolly LM Reid GE Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteinsCell2000 1024353
Not in our library10.1016/s0092-8674(00)00009-x
163.
Du C Fang M Li Y Li L Wang X Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibitionCell2000 1023342
Not in our library10.1016/s0092-8674(00)00008-8
164.
Van Loo G Demol H van Gurp M Hoorelbeke B Schotte P Beyaert R A matrix-assisted laser desorption ionization post-source decay (MALDI-PSD) analysis of proteins released from isolated liver mitochondria treated with recombinant truncated BidCell Death Differ2002 9301308
Not in our library10.1038/sj.cdd.4400966
165.
Galluzzi L Kroemer G Necroptosis: a specialized pathway of programmed necrosisCell2008 13511611163
Not in our library10.1016/j.cell.2008.12.004
166.
Zhang DW Shao J Lin J Zhang N Lu BJ Lin SC RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosisScience2009 325332336
Not in our library10.1126/science.1172308
167.
Cho YS Challa S Moquin D Genga R Ray TD Guildford M Phosphorylation-driven assembly of the RIP1–RIP3 complex regulates programmed necrosis and virus-induced inflammationCell2009 13711121123
Not in our library10.1016/j.cell.2009.05.037
168.
He S Wang L Miao L Wang T Du F Zhao L Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alphaCell2009 13711001111
Not in our library10.1016/j.cell.2009.05.021
169.
Newton K Dugger DL Wickliffe KE Kapoor N de Almagro MC Vucic D Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosisScience2014 34313571360
Not in our library10.1126/science.1249361
170.
Dondelinger Y Declercq W Montessuit S Roelandt R Goncalves A Bruggeman I MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphatesCell Rep2014 7971981
Not in our library10.1016/j.celrep.2014.04.026
171.
Wang H Sun L Su L Rizo J Liu L Wang LF Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3Mol Cell2014 54133146
Not in our library10.1016/j.molcel.2014.03.003
172.
Moujalled DM Cook WD Murphy JM Vaux DL Necroptosis induced by RIPK3 requires MLKL but not Drp1Cell Death Dis2014 5e1086
Not in our library10.1038/cddis.2014.18
173.
Galluzzi L Kepp O Kroemer G MLKL regulates necrotic plasma membrane permeabilizationCell Res2014 24139140
Not in our library10.1038/cr.2014.8
174.
Chen X Li W Ren J Huang D He WT Song Y Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell deathCell Res2014 24105121
Not in our library10.1038/cr.2013.171
175.
Cai Z Jitkaew S Zhao J Chiang HC Choksi S Liu J Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosisNat Cell Biol2014 165565
Not in our library10.1038/ncb2883
176.
Murphy JM Czabotar PE Hildebrand JM Lucet IS Zhang JG Alvarez-Diaz S The pseudokinase MLKL mediates necroptosis via a molecular switch mechanismImmunity2013 39443453
Not in our library10.1016/j.immuni.2013.06.018
177.
Wu J Huang Z Ren J Zhang Z He P Li Y Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosisCell Res2013 239941006
Not in our library10.1038/cr.2013.91
178.
Zhao J Jitkaew S Cai Z Choksi S Li Q Luo J Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosisProc Natl Acad Sci USA2012 10953225327
Not in our library10.1073/pnas.1200012109
179.
Sun L Wang H Wang Z He S Chen S Liao D Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinaseCell2012 148213227
Not in our library10.1016/j.cell.2011.11.031
180.
Orozco S Yatim N Werner MR Tran H Gunja SY Tait SW RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosisCell Death Differ2014 e-pub ahead of print 6 June 2014
Not in our library10.1038/cdd.2014.76
181.
Moujalled DM Cook WD Okamoto T Murphy J Lawlor KE Vince JE TNF can activate RIPK3 and cause programmed necrosis in the absence of RIPK1Cell Death Dis2013 4e465
Not in our library10.1038/cddis.2012.201
182.
Kaiser WJ Sridharan H Huang C Mandal P Upton JW Gough PJ Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKLJ Biol Chem2013 2883126831279
Not in our library10.1074/jbc.m113.462341
183.
Dillon CP Weinlich R Rodriguez DA Cripps JG Quarato G Gurung P RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3Cell2014 15711891202
Not in our library10.1016/j.cell.2014.04.018
184.
Tenev T Bianchi K Darding M Broemer M Langlais C Wallberg F The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPsMol Cell2011 43432448
Not in our library10.1016/j.molcel.2011.06.006
185.
Rickard JA O'Donnell JA Evans JM Lalaoui N Poh AR Rogers T RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesisCell2014 15711751188
Not in our library10.1016/j.cell.2014.04.019
186.
Kaiser WJ Daley-Bauer LP Thapa RJ Mandal P Berger SB Huang C RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturitionProc Natl Acad Sci USA2014 11177537758
Not in our library10.1073/pnas.1401857111
187.
Upton JW Kaiser WJ Mocarski ES DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRACell Host Microbe2012 11290297
Not in our library10.1016/j.chom.2012.01.016
188.
Basit F Cristofanon S Fulda S Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranesCell Death Differ2013 2011611173
Not in our library10.1038/cdd.2013.45
189.
Widespread Mitochondrial Depletion via Mitophagy Does Not Compromise Necroptosis · 2013
Not checked
190.
Wang Z Jiang H Chen S Du F Wang X The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathwaysCell2012 148228243
Not in our library10.1016/j.cell.2011.11.030
191.
Vince JE Wong WW Gentle I Lawlor KE Allam R O'Reilly L Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activationImmunity2012 36215227
Not in our library10.1016/j.immuni.2012.01.012
192.
Dondelinger Y Aguileta MA Goossens V Dubuisson C Grootjans S Dejardin E RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibitionCell Death Differ2013 2013811392
Not in our library10.1038/cdd.2013.94
193.
Vanlangenakker N Vanden Berghe T Bogaert P Laukens B Zobel K Deshayes K cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent reactive oxygen species productionCell Death Differ2011 18656665
Not in our library10.1038/cdd.2010.138
194.
O'Donnell MA Perez-Jimenez E Oberst A Ng A Massoumi R Xavier R Caspase 8 inhibits programmed necrosis by processing CYLDNat Cell Biol2011 1314371442
Not in our library10.1038/ncb2362
195.
Green DR Oberst A Dillon CP Weinlich R Salvesen GS RIPK-dependent necrosis and its regulation by caspases: a mystery in five actsMol Cell2011 44916
Not in our library10.1016/j.molcel.2011.09.003
196.
Weinlich R Dillon CP Green DR Ripped to deathTrends Cell Biol2011 21630637
Not in our library10.1016/j.tcb.2011.09.002
197.
Oberst A Dillon CP Weinlich R McCormick LL Fitzgerald P Pop C Catalytic activity of the caspase-8–FLIP(L) complex inhibits RIPK3-dependent necrosisNature2011 471363367
Not in our library10.1038/nature09852
198.
Wajant H The Fas signaling pathway: more than a paradigmScience2002 29616351636
Not in our library10.1126/science.1071553
199.
Chinnaiyan AM Tepper CG Seldin MF O'Rourke K Kischkel FC Hellbardt S FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosisJ Biol Chem1996 27149614965
Not in our library10.1074/jbc.271.9.4961
200.
Chinnaiyan AM O'Rourke K Tewari M Dixit VM FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosisCell1995 81505512
Not in our library10.1016/0092-8674(95)90071-3
201.
Irmler M Thome M Hahne M Schneider P Hofmann K Steiner V Inhibition of death receptor signals by cellular FLIPNature1997 388190195
Not in our library10.1038/40657
202.
Muzio M Chinnaiyan AM Kischkel FC O'Rourke K Shevchenko A Ni J FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complexCell1996 85817827
Not in our library10.1016/s0092-8674(00)81266-0
203.
Kischkel FC Hellbardt S Behrmann I Germer M Pawlita M Krammer PH Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptorEMBO J1995 1455795588
Not in our library10.1002/j.1460-2075.1995.tb00245.x
204.
Vandenabeele P Melino G The flick of a switch: which death program to chooseCell Death Differ2012 1910931095
Not in our library10.1038/cdd.2012.65
205.
Tait SW Ichim G Green DR Die another way – non-apoptotic mechanisms of cell deathJ Cell Sci2014 12721352144
Not in our library10.1242/jcs.093575
206.
Cook WD Moujalled DM Ralph TJ Lock P Young SN Murphy JM RIPK1- and RIPK3-induced cell death mode is determined by target availabilityCell Death Differ2014 e-pub ahead of print 6 June 2014
Not in our library10.1038/cdd.2014.70
207.
Morioka S Broglie P Omori E Ikeda Y Takaesu G Matsumoto K TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulationJ Cell Biol2014 204607623
Not in our library10.1083/jcb.201305070
208.
Pietrocola F Izzo V Niso-Santano M Vacchelli E Galluzzi L Maiuri MC Regulation of autophagy by stress-responsive transcription factorsSemin Cancer Biol2013 23310322
Not in our library10.1016/j.semcancer.2013.05.008
209.
Shin JH Min SH Kim SJ Kim YI Park J Lee HK TAK1 regulates autophagic cell death by suppressing the phosphorylation of p70 S6 kinase 1Sci Rep2013 31561
Not in our library10.1038/srep01561
210.
Criollo A Niso-Santano M Malik SA Michaud M Morselli E Marino G Inhibition of autophagy by TAB2 and TAB3EMBO J2011 3049084920
Not in our library10.1038/emboj.2011.413
211.
Ben-Neriah Y Karin M Inflammation meets cancer, with NF-kappaB as the matchmakerNat Immunol2011 12715723
Not in our library10.1038/ni.2060
212.
Vallabhapurapu S Karin M Regulation and function of NF-kappaB transcription factors in the immune systemAnnu Rev Immunol2009 27693733
Not in our library10.1146/annurev.immunol.021908.132641
213.
Bertrand MJ Milutinovic S Dickson KM Ho WC Boudreault A Durkin J cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitinationMol Cell2008 30689700
Not in our library10.1016/j.molcel.2008.05.014
214.
Kroemer G Galluzzi L Brenner C Mitochondrial membrane permeabilization in cell deathPhysiol Rev2007 8799163
Not in our library10.1152/physrev.00013.2006
215.
Galluzzi L Kroemer G Mitochondrial apoptosis without VDACNat Cell Biol2007 9487489
Not in our library10.1038/ncb0507-487
216.
Baines CP Kaiser RA Sheiko T Craigen WJ Molkentin JD Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell deathNat Cell Biol2007 9550555
Not in our library10.1038/ncb1575
217.
Vaseva AV Marchenko ND Ji K Tsirka SE Holzmann S Moll UM P53 opens the mitochondrial permeability transition pore to trigger necrosisCell2012 14915361548
Not in our library10.1016/j.cell.2012.05.014
218.
Verrier F Mignotte B Jan G Brenner C Study of PTPC composition during apoptosis for identification of viral protein targetAnn NY Acad Sci2003 1010126142
Not in our library10.1196/annals.1299.022
219.
Brenner C Moulin M Physiological roles of the permeability transition poreCirc Res2012 11112371247
Not in our library10.1161/circresaha.112.265942
220.
Brenner C Grimm S The permeability transition pore complex in cancer cell deathOncogene2006 2547444756
Not in our library10.1038/sj.onc.1209609
221.
Lemasters JJ Theruvath TP Zhong Z Nieminen AL Mitochondrial calcium and the permeability transition in cell deathBiochim Biophys Acta2009 178713951401
Not in our library10.1016/j.bbabio.2009.06.009
222.
Tait SW Green DR Mitochondrial regulation of cell deathCold Spring Harb Perspect Biol2013 5
Not in our library10.1101/cshperspect.a008706
223.
Tait SW Green DR Mitochondria and cell signallingJ Cell Sci2012 125807815
Not in our library10.1242/jcs.099234
224.
Tait SW Green DR Mitochondria and cell death: outer membrane permeabilization and beyondNat Rev Mol Cell Biol2010 11621632
Not in our library10.1038/nrm2952
225.
Tait SW Parsons MJ Llambi F Bouchier-Hayes L Connell S Munoz-Pinedo C Resistance to caspase-independent cell death requires persistence of intact mitochondriaDev Cell2010 18802813
Not in our library10.1016/j.devcel.2010.03.014
226.
Li Y Johnson N Capano M Edwards M Crompton M Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosisBiochem J2004 383101109
Not in our library10.1042/bj20040669
227.
Kroemer G Martin SJ Caspase-independent cell deathNat Med2005 11725730
Not in our library10.1038/nm1263
228.
Dam AD Mitchell AS Quadrilatero J Induction of mitochondrial biogenesis protects against caspase-dependent and caspase-independent apoptosis in L6 myoblastsBiochim Biophys Acta2013 183334263435
Not in our library10.1016/j.bbamcr.2013.04.014
229.
Bonora M Wieckowski MR Chinopoulos C Kepp O Kroemer G Galluzzi L Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transitionOncogene2014 e-pub ahead of print 14 April 2014
Not in our library10.1038/onc.2014.96
230.
Zhivotovsky B Galluzzi L Kepp O Kroemer G Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machineryCell Death Differ2009 1614191425
Not in our library10.1038/cdd.2009.118
231.
Giorgio V von Stockum S Antoniel M Fabbro A Fogolari F Forte M Dimers of mitochondrial ATP synthase form the permeability transition poreProc Natl Acad Sci USA2013 11058875892
Not in our library10.1073/pnas.1217823110
232.
Bonora M Bononi A De Marchi E Giorgi C Lebiedzinska M Marchi S Role of the c subunit of the FO ATP synthase in mitochondrial permeability transitionCell Cycle2013 12674683
Not in our library10.4161/cc.23599
233.
Campanella M Parker N Tan CH Hall AM Duchen MR IF(1): setting the pace of the F(1)F(o)-ATP synthaseTrends Biochem Sci2009 34343350
Not in our library10.1016/j.tibs.2009.03.006
234.
Alavian KN Beutner G Lazrove E Sacchetti S Park HA Licznerski P An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition poreProc Natl Acad Sci USA2014 1111058010585
Not in our library10.1073/pnas.1401591111
235.
Pan X Liu J Nguyen T Liu C Sun J Teng Y The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporterNat Cell Biol2013 1514641472
Not in our library10.1038/ncb2868
236.
Murphy E Pan X Nguyen T Liu J Holmstrom KM Finkel T Unresolved questions from the analysis of mice lacking MCU expressionBiochem Biophys Res Commun2014 449384385
Not in our library10.1016/j.bbrc.2014.04.144
237.
Fatokun AA Dawson VL Dawson TM Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunitiesBr J Pharmacol2014 17120002016
Not in our library10.1111/bph.12416
238.
Wang Y Kim NS Haince JF Kang HC David KK Andrabi SA Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos)Sci Signal2011 4ra20
Not in our library10.1126/scisignal.2000902
239.
Yu SW Andrabi SA Wang H Kim NS Poirier GG Dawson TM Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell deathProc Natl Acad Sci USA2006 1031831418319
Not in our library10.1073/pnas.0606528103
240.
Yu SW Wang H Poitras MF Coombs C Bowers WJ Federoff HJ Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factorScience2002 297259263
Not in our library10.1126/science.1072221
241.
TNF-induced necroptosis and PARP-1-mediated necrosis represent distinct routes to programmed necrotic cell death · 2013
No notice
242.
Park EJ Min KJ Lee TJ Yoo YH Kim YS Kwon TK beta-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cellsCell Death Dis2014 5e1230
Not in our library10.1038/cddis.2014.202
243.
Vanlangenakker N Vanden Berghe T Vandenabeele P Many stimuli pull the necrotic trigger, an overviewCell Death Differ2012 197586
Not in our library10.1038/cdd.2011.164
244.
Skouta R Dixon SJ Wang J Dunn DE Orman M Shimada K Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease modelsJ Am Chem Soc2014 13645514556
Not in our library10.1021/ja411006a
245.
Yang WS SriRamaratnam R Welsch ME Shimada K Skouta R Viswanathan VS Regulation of ferroptotic cancer cell death by GPX4Cell2014 156317331
Not in our library10.1016/j.cell.2013.12.010
246.
Dixon SJ Stockwell BR The role of iron and reactive oxygen species in cell deathNat Chem Biol2014 10917
Not in our library10.1038/nchembio.1416
247.
Dixon SJ Lemberg KM Lamprecht MR Skouta R Zaitsev EM Gleason CE Ferroptosis: an iron-dependent form of nonapoptotic cell deathCell2012 14910601072
Not in our library10.1016/j.cell.2012.03.042
248.
Dolma S Lessnick SL Hahn WC Stockwell BR Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cellsCancer Cell2003 3285296
Not in our library10.1016/s1535-6108(03)00050-3
249.
Tan S Schubert D Maher P Oxytosis: a novel form of programmed cell deathCurr Top Med Chem2001 1497506
Not in our library10.2174/1568026013394741
250.
Noch E Khalili K Molecular mechanisms of necrosis in glioblastoma: the role of glutamate excitotoxicityCancer Biol Ther2009 817911797
Not in our library10.4161/cbt.8.19.9762
251.
Arundine M Tymianski M Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicityCell Calcium2003 34325337
Not in our library10.1016/s0143-4160(03)00141-6
252.
Marino G Niso-Santano M Baehrecke EH Kroemer G Self-consumption: the interplay of autophagy and apoptosisNat Rev Mol Cell Biol2014 158194
Not in our library10.1038/nrm3735
253.
Grander D Kharaziha P Laane E Pokrovskaja K Panaretakis T Autophagy as the main means of cytotoxicity by glucocorticoids in hematological malignanciesAutophagy2009 511981200
Not in our library10.4161/auto.5.8.10122
254.
Laane E Tamm KP Buentke E Ito K Kharaziha P Oscarsson J Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagyCell Death Differ2009 1610181029
Not in our library10.1038/cdd.2009.46
255.
Liu Y Shoji-Kawata S Sumpter RM Jr Wei Y Ginet V Zhang L Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia–ischemiaProc Natl Acad Sci USA2013 1102036420371
Not in our library10.1073/pnas.1319661110
256.
Varma H Gangadhar NM Letso RR Wolpaw AJ Sriramaratnam R Stockwell BR Identification of a small molecule that induces ATG5-and-cathepsin-l-dependent cell death and modulates polyglutamine toxicityExp Cell Res2013 31917591773
Not in our library10.1016/j.yexcr.2013.03.019
257.
Elgendy M Sheridan C Brumatti G Martin SJ Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survivalMol Cell2011 422335
Not in our library10.1016/j.molcel.2011.02.009
258.
Nihira K Miki Y Ono K Suzuki T Sasano H An inhibition of p62/SQSTM1 caused autophagic cell death of several human carcinoma cellsCancer Sci2014 105568575
Not in our library10.1111/cas.12396
259.
Chen SY Chiu LY Maa MC Wang JS Chien CL Lin WW zVAD-induced autophagic cell death requires c-Src-dependent ERK and JNK activation and reactive oxygen species generationAutophagy2011 7217228
Not in our library10.4161/auto.7.2.14212
260.
Munoz-Pinedo C Martin SJ Autosis: a new addition to the cell death tower of babelCell Death Dis2014 5e1319
Not in our library10.1038/cddis.2014.246
261.
Prabhakaran K Li L Borowitz JL Isom GE Caspase inhibition switches the mode of cell death induced by cyanide by enhancing reactive oxygen species generation and PARP-1 activationToxicol Appl Pharmacol2004 195194202
Not in our library10.1016/j.taap.2003.11.012
262.
McCarthy NJ Whyte MK Gilbert CS Evan GI Inhibition of Ced-3/ICE-related proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bcl-2 homologue BakJ Cell Biol1997 136215227
Not in our library10.1083/jcb.136.1.215
263.
Steinhart L Belz K Fulda S Smac mimetic and demethylating agents synergistically trigger cell death in acute myeloid leukemia cells and overcome apoptosis resistance by inducing necroptosisCell Death Dis2013 4e802
Not in our library10.1038/cddis.2013.320
264.
Dunai ZA Imre G Barna G Korcsmaros T Petak I Bauer PI Staurosporine induces necroptotic cell death under caspase-compromised conditions in U937 cellsPLoS One2012 7e41945
Not in our library10.1371/journal.pone.0041945
265.
Minina EA Filonova LH Fukada K Savenkov EI Gogvadze V Clapham D Autophagy and metacaspase determine the mode of cell death in plantsJ Cell Biol2013 203917927
Not in our library10.1083/jcb.201307082
266.
Chen WW Yu H Fan HB Zhang CC Zhang M Zhang C RIP1 mediates the protection of geldanamycin on neuronal injury induced by oxygen-glucose deprivation combined with zVAD in primary cortical neuronsJ Neurochem2012 1207077
Not in our library10.1111/j.1471-4159.2011.07526.x
267.
Han W Xie J Fang Y Wang Z Pan H Nec-1 enhances shikonin-induced apoptosis in leukemia cells by inhibition of RIP-1 and ERK1/2Int J Mol Sci2012 1372127225
Not in our library10.3390/ijms13067212
268.
Luo JL Kamata H Karin M IKK/NF-kappaB signaling: balancing life and death – a new approach to cancer therapyJ Clin Invest2005 11526252632
Not in our library10.1172/jci26322
269.
Hughes MA Harper N Butterworth M Cain K Cohen GM MacFarlane M Reconstitution of the death-inducing signaling complex reveals a substrate switch that determines CD95-mediated death or survivalMol Cell2009 35265279
Not in our library10.1016/j.molcel.2009.06.012
270.
Ide T Brown-Endres L Chu K Ongusaha PP Ohtsuka T El-Deiry WS GAMT, a p53-inducible modulator of apoptosis, is critical for the adaptive response to nutrient stressMol Cell2009 36379392
Not in our library10.1016/j.molcel.2009.09.031
271.
Khalil H Bertrand MJ Vandenabeele P Widmann C Caspase-3 and RasGAP: a stress-sensing survival/demise switchTrends Cell Biol2014 248389
Not in our library10.1016/j.tcb.2013.08.002
272.
Nikoletopoulou V Markaki M Palikaras K Tavernarakis N Crosstalk between apoptosis, necrosis and autophagyBiochim Biophys Acta2013 183334483459
Not in our library10.1016/j.bbamcr.2013.06.001
273.
Modeling a Snap-Action, Variable-Delay Switch Controlling Extrinsic Cell Death · 2008
No notice
274.
Linkermann A Brasen JH Darding M Jin MK Sanz AB Heller JO Two independent pathways of regulated necrosis mediate ischemia-reperfusion injuryProc Natl Acad Sci USA2013 1101202412029
Not in our library10.1073/pnas.1305538110
275.
Linkermann A Brasen JH De Zen F Weinlich R Schwendener RA Green DR Dichotomy between RIP1- and RIP3-mediated necroptosis in tumor necrosis factor-alpha-induced shockMol Med2012 18577586
Not in our library10.2119/molmed.2011.00423
276.
Duprez L Takahashi N Van Hauwermeiren F Vandendriessche B Goossens V Vanden Berghe T RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndromeImmunity2011 35908918
Not in our library10.1016/j.immuni.2011.09.020
277.
Trichonas G Murakami Y Thanos A Morizane Y Kayama M Debouck CM Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosisProc Natl Acad Sci USA2010 1072169521700
Not in our library10.1073/pnas.1009179107
278.
Kim SJ Li J Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microgliaCell Death Dis2013 4e716
Not in our library10.1038/cddis.2013.238
279.
Yoshida H Kong YY Yoshida R Elia AJ Hakem A Hakem R Apaf1 is required for mitochondrial pathways of apoptosis and brain developmentCell1998 94739750
Not in our library10.1016/s0092-8674(00)81733-x
280.
Cecconi F Alvarez-Bolado G Meyer BI Roth KA Gruss P Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian developmentCell1998 94727737
Not in our library10.1016/s0092-8674(00)81732-8
281.
Hakem R Hakem A Duncan GS Henderson JT Woo M Soengas MS Differential requirement for caspase 9 in apoptotic pathways in vivoCell1998 94339352
Not in our library10.1016/s0092-8674(00)81477-4
282.
Kuida K Haydar TF Kuan CY Gu Y Taya C Karasuyama H Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9Cell1998 94325337
Not in our library10.1016/s0092-8674(00)81476-2
283.
Woo M Hakem R Soengas MS Duncan GS Shahinian A Kagi D Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changesGenes Dev1998 12806819
Not in our library10.1101/gad.12.6.806
284.
Kuida K Zheng TS Na S Kuan C Yang D Karasuyama H Decreased apoptosis in the brain and premature lethality in CPP32-deficient miceNature1996 384368372
Not in our library10.1038/384368a0
285.
Li J Yuan J Caspases in apoptosis and beyondOncogene2008 2761946206
Not in our library10.1038/onc.2008.297
286.
Degterev A Boyce M Yuan J A decade of caspasesOncogene2003 2285438567
Not in our library10.1038/sj.onc.1207107
287.
Honarpour N Du C Richardson JA Hammer RE Wang X Herz J Adult Apaf-1-deficient mice exhibit male infertilityDev Biol2000 218248258
Not in our library10.1006/dbio.1999.9585
288.
Wei MC Zong WX Cheng EH Lindsten T Panoutsakopoulou V Ross AJ Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and deathScience2001 292727730
Not in our library10.1126/science.1059108
289.
Puthalakath H Strasser A Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteinsCell Death Differ2002 9505512
Not in our library10.1038/sj.cdd.4400998
290.
Puthalakath H Villunger A O'Reilly LA Beaumont JG Coultas L Cheney RE Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikisScience2001 29318291832
Not in our library10.1126/science.1062257
291.
Bouillet P Purton JF Godfrey DI Zhang LC Coultas L Puthalakath H BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytesNature2002 415922926
Not in our library10.1038/415922a
292.
Lindsten T Ross AJ King A Zong WX Rathmell JC Shiels HA The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissuesMol Cell2000 613891399
Not in our library10.1016/s1097-2765(00)00136-2
293.
Labi V Woess C Tuzlak S Erlacher M Bouillet P Strasser A Deregulated cell death and lymphocyte homeostasis cause premature lethality in mice lacking the BH3-only proteins Bim and BmfBlood2014 12326522662
Not in our library10.1182/blood-2013-11-537217
294.
O'Brien RJ Wong PC Amyloid precursor protein processing and Alzheimer's diseaseAnnu Rev Neurosci2011 34185204
Not in our library10.1146/annurev-neuro-061010-113613
295.
D'Amelio M Sheng M Cecconi F Caspase-3 in the central nervous system: beyond apoptosisTrends Neurosci2012 35700709
Not in our library10.1016/j.tins.2012.06.004
296.
Bredesen DE Rao RV Mehlen P Cell death in the nervous systemNature2006 443796802
Not in our library10.1038/nature05293
297.
Nakamura T Wang L Wong CC Scott FL Eckelman BP Han X Transnitrosylation of XIAP regulates caspase-dependent neuronal cell deathMol Cell2010 39184195
Not in our library10.1016/j.molcel.2010.07.002
298.
Burguillos MA Deierborg T Kavanagh E Persson A Hajji N Garcia-Quintanilla A Caspase signalling controls microglia activation and neurotoxicityNature2011 472319324
Not in our library10.1038/nature09788
299.
Barut S Unlu YA Karaoglan A Tuncdemir M Dagistanli FK Ozturk M The neuroprotective effects of z-DEVD.fmk, a caspase-3 inhibitor, on traumatic spinal cord injury in ratsSurg Neurol2005 64213220discussion 220.
Not in our library10.1016/j.surneu.2005.03.042
300.
Knoblach SM Alroy DA Nikolaeva M Cernak I Stoica BA Faden AI Caspase inhibitor z-DEVD-fmk attenuates calpain and necrotic cell death in vitro and after traumatic brain injuryJ Cereb Blood Flow Metab2004 2411191132
Not in our library10.1097/01.wcb.0000138664.17682.32
301.
Renolleau S Fau S Goyenvalle C Joly LM Chauvier D Jacotot E Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for genderJ Neurochem2007 10010621071
Not in our library10.1111/j.1471-4159.2006.04269.x
302.
Endres M Namura S Shimizu-Sasamata M Waeber C Zhang L Gomez-Isla T Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase familyJ Cereb Blood Flow Metab1998 18238247
Not in our library10.1097/00004647-199803000-00002
303.
Han BH Xu D Choi J Han Y Xanthoudakis S Roy S Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic–ischemic brain injuryJ Biol Chem2002 2773012830136
Not in our library10.1074/jbc.m202931200
304.
Han W Sun Y Wang X Zhu C Blomgren K Delayed, long-term administration of the caspase inhibitor Q-VD-OPh reduced brain injury induced by neonatal hypoxia–ischemiaDev Neurosci2014 366472
Not in our library10.1159/000357939
305.
Wolf BB Goldstein JC Stennicke HR Beere H Amarante-Mendes GP Salvesen GS Calpain functions in a caspase-independent manner to promote apoptosis-like events during platelet activationBlood1999 9416831692
Not in our library
306.
Schotte P Declercq W Van Huffel S Vandenabeele P Beyaert R Non-specific effects of methyl ketone peptide inhibitors of caspasesFEBS Lett1999 442117121
Not in our library10.1016/s0014-5793(98)01640-8
307.
Garrido C Galluzzi L Brunet M Puig PE Didelot C Kroemer G Mechanisms of cytochrome c release from mitochondriaCell Death Differ2006 1314231433
Not in our library10.1038/sj.cdd.4401950
308.
Mondragon L Galluzzi L Mouhamad S Orzaez M Vicencio JM Vitale I A chemical inhibitor of Apaf-1 exerts mitochondrioprotective functions and interferes with the intra-S-phase DNA damage checkpointApoptosis2009 14182190
Not in our library10.1007/s10495-008-0310-x
309.
Slee EA Keogh SA Martin SJ Cleavage of BID during cytotoxic drug and UV radiation-induced apoptosis occurs downstream of the point of Bcl-2 action and is catalysed by caspase-3: a potential feedback loop for amplification of apoptosis-associated mitochondrial cytochrome c releaseCell Death Differ2000 7556565
Not in our library10.1038/sj.cdd.4400689
310.
Lakhani SA Masud A Kuida K Porter GA Jr Booth CJ Mehal WZ Caspases 3 and 7: key mediators of mitochondrial events of apoptosisScience2006 311847851
Not in our library10.1126/science.1115035
311.
Krysko O Love Aaes T Bachert C Vandenabeele P Krysko DV Many faces of DAMPs in cancer therapyCell Death Dis2013 4e631
Not in our library10.1038/cddis.2013.156
312.
Kaczmarek A Vandenabeele P Krysko DV Necroptosis: the release of damage-associated molecular patterns and its physiological relevanceImmunity2013 38209223
Not in our library10.1016/j.immuni.2013.02.003
313.
Hou W Zhang Q Yan Z Chen R Zeh Iii HJ Kang R Strange attractors: DAMPs and autophagy link tumor cell death and immunityCell Death Dis2013 4e966
Not in our library10.1038/cddis.2013.493
314.
Knight KR Zhang B Morrison WA Stewart AG Ischaemia-reperfusion injury in mouse skeletal muscle is reduced by N omega-nitro-L-arginine methyl ester and dexamethasoneEur J Pharmacol1997 332273278
Not in our library10.1016/s0014-2999(97)01101-1
315.
Kumar S Allen DA Kieswich JE Patel NS Harwood S Mazzon E Dexamethasone ameliorates renal ischemia–reperfusion injuryJ Am Soc Nephrol2009 2024122425
Not in our library10.1681/asn.2008080868
316.
Zhang W Xing J Liu D Gan X Gao W Hei Z Dexamethasone pretreatment alleviates intestinal ischemia–reperfusion injuryJ Surg Res2013 185851860
Not in our library10.1016/j.jss.2013.07.049
317.
Kraft P Gob E Schuhmann MK Gobel K Deppermann C Thielmann I FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-inflammation but not by direct neuroprotectionStroke2013 4432023210
Not in our library10.1161/strokeaha.113.002880
318.
Pacher P Szabo C Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitorsCardiovasc Drug Rev2007 25235260
Not in our library10.1111/j.1527-3466.2007.00018.x
319.
del Moral RM Gomez-Morales M Hernandez-Cortes P Aguilar D Caballero T Aneiros-Fernandez J PARP inhibition attenuates histopathological lesion in ischemia/reperfusion renal mouse model after cold prolonged ischemiaScientific World J2013 2013486574
Not in our library10.1155/2013/486574
320.
Li X Klaus JA Zhang J Xu Z Kibler KK Andrabi SA Contributions of poly(ADP-ribose) polymerase-1 and -2 to nuclear translocation of apoptosis-inducing factor and injury from focal cerebral ischemiaJ Neurochem2010 11310121022
Not in our library10.1111/j.1471-4159.2010.06667.x
321.
Curtin NJ Szabo C Therapeutic applications of PARP inhibitors: anticancer therapy and beyondMol Aspects Med2013 3412171256
Not in our library10.1016/j.mam.2013.01.006
322.
Vanden Berghe T Vanlangenakker N Parthoens E Deckers W Devos M Festjens N Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration featuresCell Death Differ2010 17922930
Not in our library10.1038/cdd.2009.184
323.
Tang HL Tang HM Mak KH Hu S Wang SS Wong KM Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic responseMol Biol Cell2012 2322402252
Not in our library10.1091/mbc.e11-11-0926
324.
Tang HL Tang HM Hardwick JM Fung MC Strategies for tracking anastasis, a cell survival phenomenon that reverses apoptosisJ Vis Exp2014 2014e51964
Not in our library10.3791/51964
325.
Zhu D Cardenas ME Heitman J Calcineurin mutants render T lymphocytes resistant to cyclosporin AMol Pharmacol1996 50506511
Not in our library
326.
Fruman DA Klee CB Bierer BE Burakoff SJ Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin AProc Natl Acad Sci USA1992 8936863690
Not in our library10.1073/pnas.89.9.3686
327.
Gomes LC Di Benedetto G Scorrano L During autophagy mitochondria elongate, are spared from degradation and sustain cell viabilityNat Cell Biol2011 13589598
Not in our library10.1038/ncb2220
328.
Brookes PS Yoon Y Robotham JL Anders MW Sheu SS Calcium, ATP, and ROS: a mitochondrial love–hate triangleAm J Physiol Cell Physiol2004 287C817C833
Not in our library10.1152/ajpcell.00139.2004
329.
Zimmermann KC Ricci JE Droin NM Green DR The role of ARK in stress-induced apoptosis in Drosophila cellsJ Cell Biol2002 15610771087
Not in our library10.1083/jcb.20112068
330.
Kanuka H Sawamoto K Inohara N Matsuno K Okano H Miura M Control of the cell death pathway by Dapaf-1, a Drosophila Apaf-1/CED-4-related caspase activatorMol Cell1999 4757769
Not in our library10.1016/s1097-2765(00)80386-x
331.
Xue D Horvitz HR Inhibition of the Caenorhabditis elegans cell-death protease CED-3 by a CED-3 cleavage site in baculovirus p35 proteinNature1995 377248251
Not in our library10.1038/377248a0
332.
Daish TJ Mills K Kumar S Drosophila caspase DRONC is required for specific developmental cell death pathways and stress-induced apoptosisDev Cell2004 7909915
Not in our library10.1016/j.devcel.2004.09.018
333.
Fraser AG McCarthy NJ Evan GI drICE is an essential caspase required for apoptotic activity in Drosophila cellsEMBO J1997 1661926199
Not in our library10.1093/emboj/16.20.6192
334.
Song Z McCall K Steller H DCP-1, a Drosophila cell death protease essential for developmentScience1997 275536540
Not in our library10.1126/science.275.5299.536
335.
Yuan J Shaham S Ledoux S Ellis HM Horvitz HR The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzymeCell1993 75641652
Not in our library10.1016/0092-8674(93)90485-9
336.
Fan TJ Han LH Cong RS Liang J Caspase family proteases and apoptosisActa Biochim Biophys Sin (Shanghai)2005 37719727
Not in our library10.1111/j.1745-7270.2005.00108.x
337.
Martin SJ Henry CM Cullen SP A perspective on mammalian caspases as positive and negative regulators of inflammationMol Cell2012 46387397
Not in our library10.1016/j.molcel.2012.04.026

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