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Targeting CDK1 in cancer: mechanisms and implications

Qiushi Wang, Ann M. Bode, Tianshun Zhang

npj Precision Oncology · 2023 · Review · CC BY

doi:10.1038/s41698-023-00407-7 (opens in a new tab)

Abstract

Cyclin dependent kinases (CDKs) are serine/threonine kinases that are proposed as promising candidate targets for cancer treatment. These proteins complexed with cyclins play a critical role in cell cycle progression. Most CDKs demonstrate substantially higher expression in cancer tissues compared with normal tissues and, according to the TCGA database, correlate with survival rate in multiple cancer types. Deregulation of CDK1 has been shown to be closely associated with tumorigenesis. CDK1 activation plays a critical role in a wide range of cancer types; and CDK1 phosphorylation of its many substrates greatly influences their function in tumorigenesis. Enrichment of CDK1 interacting proteins with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted to demonstrate that the associated proteins participate in multiple oncogenic pathways. This abundance of evidence clearly supports CDK1 as a promising target for cancer therapy. A number of small molecules targeting CDK1 or multiple CDKs have been developed and evaluated in preclinical studies. Notably, some of these small molecules have also been subjected to human clinical trials. This review evaluates the mechanisms and implications of targeting CDK1 in tumorigenesis and cancer therapy.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Cyclin dependent kinases (CDKs) are serine/threonine kinases that form a complex with cyclin proteins, a process that is essential for full activation of their kinase activity. CDKs play critical roles in the control of cell division and modulation of transcription in response to extracellular and intracellular stimuli. CDKs are involved in many crucial processes and are associated with several disease conditions, such as Alzheimer’s disease, Parkinson’s disease, stroke, HIV, and cancer,. The CDK protein family comprises twenty kinases (CDK1-20). CDK1-6 and CDK14-18 are involved in cell cycle and CDK7-13 and CDK19-20 are associated with the function of transcription in gene control,. CDK1 is the only CDK in mammals that is essential for cell cycle progression. It promotes the G2/M and G1/S transitions, as well as G1 progression. Unrestricted cell proliferation, an indicator of malignancy, is normally driven by alterations in CDK1 activity. The expression of CDKs fluctuates cyclically throughout the cell cycle. Cancer is a disease of abnormal cell proliferation and occurs when cells evade normal growth or division restrictions. Oncogenic transformation often entails derangement of the mechanisms that ensure the stable inheritance of genes and chromosomes during mitotic cell division. CDKs play important roles in both the commitment to cell division and the quality control mechanisms that safeguard genome integrity. They represent obvious, but potentially risky, therapeutic targets in treating human cancers. In addition to presenting the frequency of overexpression in different cancer types, CDKs have been shown to function as oncogenes or were identified as frequently overexpressed secondary oncogenes in several types of cancer, including melanoma and lung cancer. In these cancers, CDKs are not the primary drivers of cancer but are overexpressed in conjunction with other oncogenes–. For instance, CDKs are highly expressed in non-small cell lung cancer with EGFR mutations. CDK/cyclin activity is mediated by physiological CDK inhibitors or CKIs. Over the last decade, substantial progress has been made in discovering and developing novel small molecule CKIs–. This area of drug discovery has adopted novel research strategies that are different from the classic reversible ATP competitive or non-competitive action modes. Traditional kinase inhibitory molecules include irreversible ATP competitive drugs, reversible and irreversible structural inhibitors, CDK degrading drugs, and inhibitory CDK binding antibodies. Newer drugs have opened an avenue to interrogate, for example, new and more challenging transcriptional CDK targets. A number of selective inhibitors or pan-inhibitors of CDK1 have been produced over past decades. Inhibition of the expression and activation of CDK1 effectively suppresses oncogenic cell function in many cancer types. Notably, some small molecules targeting CDK1 have already been studied in clinical trials. In this review, we evaluate the critical role and mechanisms of CDK1 in tumorigenesis. Additionally, we examine the current CDK1 inhibitors that have been evaluated in preclinical and clinical studies for cancer therapy.

CDK expression in cancer

According to The Cancer Genome Atlas (TCGA) UALCAN database,, CDKs are significantly upregulated in many cancerous tissues compared to normal tissues, indicating a widespread increase in their expression. (Fig. 1, Supplementary Table 1, Supplementary Fig. 1). Based on these results, CDK1, CDK2, CDK4, CDK5, and CDK7 are the top 5 CDKs that are highly expressed in cancer tissues compared to normal tissues. Overall, compared with normal tissues, the expression of CDK4 and CDK5 are higher in 18 out of 24 or 75% of the cancers listed. CDK1 is significantly higher in 17 out of 24 or 70.8% of the cancers listed and CDK2 and CDK7 are higher in 16 out of 24 or 67% of the cancers listed.

In addition, information from the database indicates that high expression of CDKs is closely correlated with the overall survival rate in 32 different cancer types (Supplementary Table 1, Fig. 2). Overall, the data indicate that the top 5 CDKs, CDK1 (11/32 or 34.4%), CDK2 (10 /32 or 31.3%), CDK6 (8/32 or 25%), CDK7 (9/32 or 28.1%), and CDK19 (8/32 or 25%), are closely associated with survival probability in various cancers.

CDKs are highly expressed in cancer tissues and closely associated with survival probability in multiple cancer types. Collectively, these results indicate that targeting CDKs, and especially CDK1, could be a critical strategy for cancer treatment. The remainder of this review focuses on mediators, substrates, and inhibitors of CDK1 in cancer.

Upstream mediators of CDK1

The upstream modulators of CDK1 (Supplementary Table 2) in cancer include various molecular factors that can positively or negatively influence CDK1 activation, amplification, transcription, and expression.

Activators of CDK1

CDK1 is essential for cell division during mitosis. It helps form the spindle and aligns chromosomes by recruiting and activating key proteins involved in kinetochore formation. CDK1 activity ensures proper chromosome orientation and segregation and is critical for the successful assembly of the mitotic apparatus and chromosome alignment. The activation of CDK1 requires phosphorylation on Thr161 or dephosphorylation on Thr14 and Tyr15,. CDK7 mediates G1 cell cycle arrest and extrinsic apoptosis by increasing phosphorylation of CDK1 at Thr161. Protein tyrosine phosphatase receptor type F (LAR) also increases focal adhesion by enhancing CDK1 activation at Thr161. Nucleolar protein 11 (NOL11) and CDK5 regulatory subunit associated protein 3 (C53) delay cell entry into mitotic phase though dephosphorylation of CDK1 on Tyr15,. Cell division cycle 25 (CDC25) is a dual-specificity phosphatase, which counteracts G2/M checkpoint activation by removing inhibitory phosphate groups (Thr14 or Tyr15) from CDK1 and are themselves negatively modulated by checkpoint kinase 1 (CHK1). CDC25 proteins include CDC25A, CDC 25B, and CDC 25C. They mediate meiosis through activation of CDK1 by dephosphorylation on Thr14 and Tyr15,–. Associated with CDC25 mediation of activation of CDK1 are several molecules, including CDK2, beclin 1 (BECN1), tetramerization domain containing 12 (KCTD12), nucleophosmin (NPM), and minichromosome maintenance 10 replication initiation factor (MCM10), each of which facilitates activation of CDK1 by mediating CDC25 activity–. For example, BECN1 translocases into the nucleus, where it interacts with CDC25C and CHK2, resulting in promotion of radiation-induced G2/M arrest through promotion of CDK1 activity. Additionally, other molecules, such as Aurora A kinase (AURKA), 6-phosphofructo-2-kinase (PFKFB3), ubiquitin C-terminal hydrolase L1 (UCH-L1), microtubule-associated serine/threonine kinase-like (MASTL), testis-specific protein Y-encoded (TSPY), karyopherin subunit beta 1 (KPNB1), and STIL centriolar assembly protein (SIL), all promote CDK1 activity (Supplementary Table 2).

Transcriptional modulation of CDK1 and upregulation of CDK1 expression (Supplementary Table 2)

E2F transcription factor (E2F)-dependent transcription controls both G1/S- and G2/M-associated genes. Specifically, E2F1, E2F2, and E2F3 enhance CDK1 transcription by binding to the positive-acting E2F site in the CDK1 promoter, which results in increased CDK1 expression. Mortality factor 4 like 1 (MRG15), a chromatin modulator, is a highly conserved protein present in complexes containing histone acetyltransferases (HATs), as well as histone deacetylases (HDACs). MRG15 acts in the HAT complex through its acetylation of histone H4 at the CDK1 promoter to activate transcription. The cysteine-rich CXC domain of Lin-54 DREAM MuvB core complex component (LIN54) is a novel DNA-binding domain that binds to the CDK1 promoter in a sequence-specific manner. Besides directly binding with the CDK1 promoter, several molecules also modulate CDK1 transcriptional activation. For example, CDK1 is a direct transcriptional target of centromere-associated protein E (CENPE) in primary pulmonary artery smooth muscle cells. The overexpression of CENPE significantly increases CDK1 promoter activity, whereas the deletion of CENPE markedly decreases promotor activity, which attenuates CDK expression. Sp1 transcription factor (SP1), initially identified as a transcription factor, plays a crucial role in normal biological processes, neoplastic development, and tumor migration. Dual-luciferase reporter assay results showed the direct effect of SP1 on the transcriptional activation of CDK1. Knockdown of ribosomal protein S9 (RPS9) inhibits the growth of human colon cancer cells at the G2/M phase by downregulating CDK1 expression at the promoter level.

Several molecules enhance tumor cell growth, migration, or invasion by upregulating the expression of CDK1 in different ways. Among them, chondroitin polymerizing factor (CHPF), co-stimulatory molecule (CD276), and papillomavirus E6 (E6) enhance CDK1 expression by increasing the expression of transcription factor E2F1. Knocking down expression of CHPF or CD276 maintains proliferation or modulates differentiation by mediating E2F1/CDK1 expression in malignant melanoma and endothelial progenitor cells, respectively,. NOP2/sun RNA methyltransferase 2 (NSUN2) and death-associated protein 5 (DAP5) promote CDK1 expression by enhancing CDK1 translation–. NSUN2 methylates CDK1 mRNA in vitro and in cells, and that methylation by NSUN2 enhances CDK1 translation influencing cell growth and survival during mitosis,. Oncogenic action of RNA binding motif protein 7 (RBM7) and histone deacetylase 6 (HDAC3) controls cell progression by stabilizing CDK1 mRNA and protein levels, respectively. RBM7 directly binds to the AU-rich elements (AREs) in the 3’-UTR of CDK1 mRNA, which contributes to the stability of CDK1 mRNA by lengthening CDK1 half-life in breast cancer. HDAC3 mediates G2/M phase progression mainly through post translational stabilization of the CDK1 protein by controlling CDK1 ubiquitination. Somatic mutations in DNA methyltransferase 3 alpha (DNMT3A) have been identified in approximately 25% of patients with LAML DNMT3A mutation that occurs in the early stages of LAML and is regarded as a pre-leukemic gene mutation. DNMT3A mutation can induce CDK1 overexpression and promote leukemogenesis. Additionally, several other molecules also mediate cell proliferation, metastasis, or survival by enhancing CDK1 expression (Supplementary Table 2).

Mediators that decrease activation of CDK1

Many molecules markedly upregulate the activity of CDK1 in tumorigenesis, whereas negative upstream mediators of CDK1 also widely exist. These negative modulators are usually tumor suppressors that inhibit CDK1 activation in tumor progression. As indicated earlier, dephosphorylation on Thr14 and Tyr15 or phosphorylation at Thr161 is required for the full activation of CDK1. Wee1-like protein kinase 1 (WEE1)– and membrane associated tyrosine/threonine 1 (MYT1) kinase– inhibit CDK1 activation by phosphorylation at Thr14 and Tyr15, and this modification plays a crucial role in the G2–M cell-cycle checkpoint arrest for DNA repair before mitotic entry. Besides these two important kinases, many other key molecules also inhibit CDK1 activation by phosphorylation of Thr14 and Tyr15 or dephosphorylation of Thr161 (Supplementary Table 2). For example, phosphatase and tensin homolog (PTEN) is one of the most important and well-studied tumor suppressor proteins. Downregulation of PTEN by siRNA in cells increases phospho-WEE1 (Ser642), but decreases phospho-CDK1 (Tyr15), resulting in decreased G2/M cell cycle arrest. Dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) demonstrates its tumor suppressive function by mediating phosphorylation of Tyr15 and Thr161 in glioblastoma cells. CDC25 is known to activate CDK1 by dephosphorylating residues Thr14 and Tyr15. Checkpoint kinase 1 (CHEK1), one of the critical transducers in DNA damage/replication checkpoints, prevents entry into mitosis through its inhibition of CDC25 and CDK1 activity,. Fibroblast growth factor 1 (FGF1) also causes dephosphorylation of the CDC25C phosphatase inducing inactivation of the cyclin B1/CDK1 complex. Kinesin family member 22 (KIF22) is a microtubule-dependent molecular motor protein with DNA-binding capacity. CDC25C is a direct transcriptional target of KIF22 and inhibition of KIF22 increases CDC25C expression and cyclin-dependent kinase 1 (CDK1) activity, resulting in delayed mitotic exit. Other proteins can also affect CDK1 activity but with no effect on phosphorylation of Thr14 and Tyr15 or dephosphorylation of Thr161. For example, death effector domain containing (DEDD) protein participates in apoptosis signaling, which inhibits activation of CDK1 but does not affect the phosphorylation status at Thr14, Tyr15, or Thr161,. Apart from these proteins, several other molecules can also inhibit CDK1 activation (Supplementary Table 2).

Mediators that decrease CDK1 expression and nuclear translocation

In addition to CDK1 activation, CDK1 expression is also tightly modulated. Eukaryotic cells utilize two major routes to effectively target a wide range of proteins for degradation, including the ubiquitin/proteasome system and the autophagy/lysosome pathway. Double-stranded RNA-activated protein kinase (PKR) is a serine/threonine interferon (IFN)-inducible kinase that plays an important role in the regulation of gene expression at both transcriptional and translational levels. PKR-mediated Tyr4-phosphorylation facilitates CDK1 ubiquitination and proteasomal degradation. CDK1 accumulation in patients’ tumors shows a negative correlation with beta-transducing repeat containing E3 ubiquitin protein ligase (BTRC) and exhibits a positive correlation with the degree of tumor malignancy. BTRC controls the lysosome-mediated degradation of CDK1, the accumulation of which correlates with tumor malignancy. Histone deacetylase 6 (HDAC6) plays a dual role in the autophagy/lysosome pathway. It controls the fusion of autophagosomes to lysosomes by promoting F-actin remodeling in a cortactin-dependent manner. In contrast, upon proteasome inhibition, HDAC6 is recruited and relocates to polyubiquitin-positive aggresomes. Ubiquitin-binding protein P62 (P62) is a key protein in the autophagic clearance of polyubiquitinated proteins. CDK1 degradation reportedly involves p62/HDAC6-mediated selective autophagy. Additionally, the TNF-like WEAK inducer of apoptosis (TWEAK), human enhancer of invasion, clone 10 (HEI10), and sialophorin (SPN) also mediate CDK1 expression by inducing CDK1 degradation, inhibiting CDK1 expression or nuclear translocation (Supplementary Table 2).

Downstream substrates of CDK1

As a serine/threonine protein kinase, CDK1 is reported to phosphorylate a number of substrates, including both tumor promotors and tumor suppressors (Supplementary Table 3).

CDK1 tumor promotor substrates

Increasing evidence suggests that CDK1 phosphorylates downstream substrates that play critical roles in cancer progression signaling pathways. The B-Raf proto-oncogene, serine/threonine kinase (BRAF), as a critical activator of the mitogen-activated protein kinase (MAPK) cascade during mitosis. CDK1/cyclin B directly phosphorylates BRAF at Ser144, which is required for mitotic activation and subsequent activation of the MAPK cascade. Extracellular signal regulated kinase 3 (ERK3) is an atypical MAPK that is suggested to play a role in cell cycle progression and cellular differentiation. CDK1 can also phosphorylate ERK3 at Thr698, which acts in a cell-cycle-dependent manner. Androgen receptor (AR) is the principal molecule in prostate cancer etiology and therapy and its re-activation remains a major challenge during treatment of prostate tumors that relapse after castration therapies. CDK1 phosphorylates the AR at Ser81 or Ser515 promoting prostate tumor progression–. Hypoxia-inducible factor 1α (HIF1A) is a major mediator of tumor physiology, and its activation is correlated with tumor progression, metastasis, and therapeutic resistance,. CDK1 stabilizes HIF1A through direct phosphorylation of Ser668 to promote tumor growth. YAP is a downstream effector of the Hippo pathway of cell-cycle control that plays important roles in tumorigenesis. CDK1 phosphorylates YAP promoting mitotic defects and cell motility and is essential for neoplastic transformation. TAZ is also a downstream effector of the Hippo pathway, which plays important roles in cancer and stem cell biology. CDK1 phosphorylation of TAZ in mitosis inhibits its oncogenic activity. Additionally, the adaptor protein, ajuba LIM protein (AJUBA), is a positive mediator of YAP oncogenic activity. CDK1 phosphorylates AJUBA at Ser119 and Ser175 during the G2/M phase of the cell cycle promoting proliferation and tumorigenesis. Besides these, other downstream oncoprotein substrates of CDK1 (Supplementary Table 3) participate in multiple signaling pathways mediating tumor progression.

Several CDK1 substrates are oncogenic transcription factors. For example, forkhead box M1B (FOXM1B) transcriptional activity requires binding of either S or M phase CDK/cyclin complexes to mediate efficient CDK1 phosphorylation of the FoxM1B Thr596 residue, which is essential for recruitment of CREB binding protein coactivator proteins. Phosphorylation of islet-1 (ISL1) at Ser269 by CDK1 increases its transcriptional activity and promotes cell proliferation in gastric cancer. Mammalian target of rapamycin (mTOR)-directed eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation promotes cap-dependent translation and tumorigenesis. CDK1-directed phosphorylation of 4E-BP1 may yield a gain of function activity, distinct from translational regulation, which may be important in tumorigenesis and mitotic centrosome function. The activating transcription factors (ATFs) belong to the activator protein 1 (AP-1) family of transcription factors. Phosphorylation of ATF7 by CDK1 at Thr51 or Thr53 in M phase is required for G2/M progression. Additionally, RUNX family transcription factor 1 (RUNX1), RUNX2, retinoid X receptor alpha (RXRA), CCAAT enhancer binding protein alpha (CEBPA), transcription factor CP2 like 1 (TFCP2L1), and octamer-binding transcription factor 4 (OCT4), are also oncogenic transcription factors mediated by CDK1 (Supplementary Table 3).

Apart from these CDK1 substrates, BCL2 apoptosis regulator (BCL2), BCL2 apoptosis regulator like 1 (BCL2L1), and dynamin 1 Like (DRP1) are phosphorylated by CDK1, mediating mitochondrial fusion and apoptosis in human cancer cells–. F-box protein 28 (FBXO28) and carboxypeptidase D (CPD) are phosphorylated by CDK1 increasing ubiquitylation promoting tumorigenesis. FBXO28 ubiquitin ligases act as one of the master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. FBXO28 activity and stability are regulated during the cell cycle by CDK1/2 phosphorylation, which is required for its efficient ubiquitylation of MYC and downstream enhancement of the MYC pathway. CDK1-mediates activation of the FBXO28 ubiquitin ligase promotes MYC-driven transcription and tumorigenesis and predicts poor survival in breast cancer. A GATA family transcription factor, GATA-binding protein 2 (GATA2), participates in cell growth and differentiation of various cells. GATA2 contains CPD, a consensus motif for ubiquitylation that includes Thr176. CDK1 phosphorylates CPD at Thr176, which increases GATA2 expression levels. Moreover, several additional molecules also demonstrate ontogenetic function mediated by CDK1 (Supplementary Table 3).

CDK1 tumor suppressor substrates

The tumor suppressor p53, an important CDK1 substrate, plays critical roles in a diversity of physiologic functions by increasing genomic stability, inhibiting cell transformation, and initiating apoptosis when DNA damage repair is defective. Cyclin B1/CDK1-mediated Ser315 phosphorylation in p53-wild-type tumor cells may provide insights for improving the efficacy of anti-cancer therapy. Moreover, the tumor protein p73 transcription factor is a member of the p53 family and participates in developmental processes and the DNA damage response. CDK1-dependent Thr86 phosphorylation represses the ability of p73 to induce endogenous p21 expression. The forkhead box O (FOXO) transcription factor FOXO1 functions as a tumor suppressor by mediating apoptosis, cell cycle arrest, and oxidative detoxification. CDK1 may contribute to tumorigenesis by promoting cell proliferation and survival through phosphorylation and inhibition of FOXO1,. Additionally, tumor suppressors caspase 8 (CASP8) and caspase 9 (CASP9) are phosphorylated by CDK1 facilitating apoptosis in cancer cells,. Some other CDK1 substrates act as tumor suppressors, including discs large MAGUK scaffold protein 1 (DLG1), F-box protein 5 (EMI1), sequestosome 1 (P62), EPH receptor A2 (EPHA2),, and vestigial like family member 4 (VGLL4). They influence tumor progression through multiple signaling pathways, including the APC, Ras/MAPK, and Hippo pathways. Besides these tumor suppressors, receptor-associated protein 80 (RAP80), inhibitor of growth family member 1 (ING1), and EMAP Like 2 (EML2) are also phosphorylated by CDK1 mediating DNA damage, cell proliferation, and migration, (Supplementary Table 3).

CDK1 cell cycle substrates

The cell cycle consists of the mitotic (M) phase and interphases, G1, S, and G2. CDK1 functions during the entire cell cycle by phosphorylating its various substrates. CDK1 is the major protein kinase that drives cells into mitosis. CDK1 phosphorylates multiple substrates including aurora kinase activator (BORA), mixed lineage leukemia-5 (MLL5), and greatwall (GWL), which all have a critical role in mitotic entry. CDK1 also acts as a mediator in mitotic exit by phosphorylation of cell division cycle associated 5 (CDCA5), and centromere protein A (CENPA). M phase consists of four basic phases including prophase, metaphase, anaphase, and telophase. CDK1 phosphorylates non-SMC condensin II complex subunit D3 (CAPD3) at Thr1415, which is required for timely chromosome condensation during prophase. Checkpoint kinase 2 (CHK2) is an essential protein kinase governing DNA damage and replication stress checkpoints. CDK1 phosphorylates CHK2 kinase in metaphase, influencing cellular morphogenesis. The spindle and kinetochore associated complex subunit 3 (SKA3) protein complex is required for accurate chromosome segregation during mitosis. SKA3 is phosphorylated by CDK1 in mitosis to promote the onset of anaphase. CDK1 phosphorylates 4E-BP1 at Ser83, which accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. Besides these, CDK1 also phosphorylates several other substrates during M phase by mediating multiple functions including spindle assembly, microtubule dynamics, and completion of cytokinesis (Supplementary Table 3). Overall, the substrates of CDK1 are critical in M phase for efficient cell division.

Following M phase, CDK1 substrates also function in the interphases of cell cycle. Fatty acyl-CoA reductase 1 (FAR1) transcription is maximal between mitosis and early G1 phase. Phosphorylation (Ser87) by CDK1 primes FAR1 for ubiquitin-mediated proteolysis. At entry into S phase, CDK1 phosphorylates WRN recQ like helicase (WRN), cell division cycle 7 (CDC7), BRCA1 DNA repair associated (BRCA1), and RAD9 checkpoint clamp component A (RAD9), influencing DNA replication and checkpoint control. In particular, CDK1-mediated phosphorylation of BRACA1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage. Telomeric repeat factor 1 (TRF1), a duplex telomeric DNA-binding protein, plays an important role in telomere metabolism. CDK1 phosphorites TRF1, which is recruited to sites of DNA damage to facilitate homologous recombination and checkpoint activation at the S/G2 phase. Additionally, CDK1 phosphorylates ELAV like RNA binding protein 1 (ELAVL1) during G2, thereby helping to retain it in the nucleus hindering its post-transcriptional function and anti-apoptotic influence. Besides these, several other molecules also play important roles in cell cycle progression (Supplementary Table 3).

CDK1 interactome and related signaling pathways

CDK1 participates in tumorigenesis by interacting with many proteins (Supplementary Tables 2 and 3) that have functions in multiple signal pathways. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential signaling pathways associated with CDK1 interacting proteins. We used the KEGG rest API (https://www.kegg.jp/kegg/rest/keggapi.html) to obtain the latest gene annotations of the KEGG pathway. The enrichment analysis was performed using the R software package, clusterProfiler (v3.14.3), to obtain results of gene set enrichment. An FDR of <0.05 was considered statistically significant. The results indicate that CDK1 integrating proteins are involved in signaling pathways in cancer, cell cycle, and microRNAs. Ten top pathways (Fig. 3A, B) were identified. Using Metascape, we then selected a subset of representative terms and converted them into a network layout. More specifically, each term is represented by a circle node, where its size is proportional to the number of input genes falling under that term, and its color represents its cluster identity (i.e., nodes of the same color belong to the same cluster). Terms with a similarity score > 0.3 are linked by an edge and the thickness of the edge represents the similarity score. The network is visualized with Cytoscape (v3.1.2) with “force-directed” layout and with edge bundled for clarity. One term from each cluster is selected to have its term description shown as a label (Fig. 3C). The same enrichment network has its nodes colored by the p value, as shown in the legend. The darker the color, the more statistically significant the node is (see legend for p value ranges, Fig. 3D). Based on the metanalysis results, signal pathways in cancer, cell cycle, and microRNAs in cancer are the top 3 pathways associated with CDK1 interacting proteins. Using the STRING database, we then obtained the interacting network of CDK1 and its interacting proteins in pathways in cancer (Fig. 3E). Collectively, CDK1 is clearly involved in multiple cancer-related pathways, suggesting the significance of CDK1 in various cancer processes.

Targeting CDK1 provides a potential strategy for attenuating cancer development

This review thus far has examined the critical role of CDK1 in cancer. The accumulated findings demonstrate that CDK1 could be a potential target for cancer prevention and therapy. In recent years, several small molecules with anticancer activity that target CDK1 and other CDKs have been identified in preclinical and clinical studies focusing on multiple cancer types. The effects of various CDK1 associated CKIs in cancer are summarized in Supplementary Tables 4 and 5.

Targeting CDK1 in preclinical studies

RO-3306– and CGP-74514A, are specific CDK1 inhibitors that effectively suppress the growth of cancer cells and patient derived xenografts (PDX). Additionally, the pan-CDK inhibitors have shown anticancer activity in preclinical studies (Supplementary Table 4).

Targeting CDK1 in clinical studies

CDKs are attractive targets against cancer and CDK inhibitors have been studied since the 1990s. Also, various clinical trials have investigated the use of CDK inhibitors in order to improve treatment of patients with virous cancer types (Supplementary Table 5). Some of the more notable inhibitors are discussed below.

BEY1107

BEY1107 (avotaciclib) is an orally active CDK1 inhibitor. A phase 1/2 clinical trial has assessed the maximum tolerated dose, safety, and efficacy of BEY1107. It is proposed to be used as a monotherapy and in combination with gemcitabine in patients with locally advanced or metastatic pancreatic cancer.

Flavopiridol

Flavopiridol (alvocidib) is a pan-CDK inhibitor that suppresses CDK1, CDK2, CDK4, CDK6, CDK7, and CDK9 with IC50s of 30, 170, 100, 60, 300, and 10 nM, respectively. Several clinical trials have been conducted for the treatment of leukemia, multiple myeloma, sarcoma, gastrointestinal stromal tumor, and other solid tumors. Flavopiridol has received “orphan drug” designation from the FDA for LAML. Previous preclinical studies suggested that flavopiridol can inhibit cancer development,. Unfortunately, it showed less efficacy in human clinical studies. In particular, flavopiridol at this dose and schedule does not have single-agent activity in patients with colorectal cancer. Trials that evaluate flavopiridol in combination with active cytotoxic drugs should help to define the role of this novel agent in colorectal cancer. Additionally, flavopiridol also exhibited certain side effects in the clinical trial. Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation, but only achieved marginal responses in relapsed myeloma. To decrease the side effects, the combination of flavopiridol with other anticancer drugs might be an effective way to enhance its efficacy.

Roniciclib

Roniciclib (BAY1000394) is an orally bioavailable pan-cyclin dependent kinase (CDK) inhibitor, with IC50s of 5–25 nM for CDK1, CDK2, CDK3, CDK4, CDK7, and CDK9. Roniciclib has been used in several clinical trials of various neoplasms and lung cancer. Based on a Phase 1 dose-escalation study of roniciclib in advanced malignancies, Roniciclib demonstrated an acceptable safety profile and moderate disease control rate in 3 days on/4 days off schedule. Roniciclib co-administered with chemotherapy in patients with extensive-disease small-cell lung cancer (ED-SCLC) demonstrated tolerability, acceptable pharmacokinetics, and promising efficacy. Unfortunately, an observed safety signal in a related phase 2 study resulted in discontinuation of the present study and termination of further development of roniciclib,.

P276-00

P276-00 (Riviciclib) is a potent CDK inhibitor and suppresses CDK1, CDK4, CDK9 activity with IC50s of 79, 63, and 20 nM, respectively. A phase 1 study was designed to determine the maximum tolerated dose, toxicity profile, pharmacokinetics, and anti-cancer activity of P276–00 given intravenously to patients with advanced refractory neoplasms,. Additional clinical studies evaluated efficacy of P276-00 in subjects with advanced malignant melanoma positive for cyclin D1 expression, advanced triple negative breast cancer, and advanced head and neck cancer,. Notably, a Phase 2, single-arm, open-label, multicenter study evaluated the efficacy and safety of P276-00 in patients with relapsed or refractory mantle cell lymphoma. Of the 13 patients, 11 experienced disease progression, 1 patient was withdrawn because of an adverse event, and 1 patient died. Given the results observed in the present study, if evaluation of CDK inhibition in MCL continues, it should be considered earlier in the disease course or as a part of combination strategies for relapsed or refractory disease. These results suggest the anticancer efficacy of P276-00; however, further investigations are still needed to confirm the anticancer effects and safety.

Dinaciclib

Dinaciclib (SCH727965) is a broad spectrum and competitive inhibitor of CDKs. It can inhibit CDK1, CDK2, CDK5, and CDK9 with IC50s of 3, 1, 1, and 4 nM, respectively. Dinaciclib has been used in several clinical trials to treat multiple cancer types such as pancreatic cancer, non-small-cell lung cancer, neoplasms, leukemia, breast cancer, myeloma, lymphoma and melanoma. Dinaciclib has demonstrated inhibitory effects in several clinical studies and showed significant clinical activity against relapsed and refractory chronic lymphocytic leukemia. Positive responses occurred in 28 (54%) of patients with a median progression-free survival of 481 days. Another study demonstrated single agent activity of dinaciclib against relapsed myeloma. The same study also showed that dinaciclib treatment demonstrated antitumor activity in 2 of 7 patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (1 confirmed and 1 unconfirmed partial response), as well as acceptable safety and tolerability. All these results suggested that dinaciclib is a promising CDK1-associated inhibitor for clinical treatment of cancer.

AT7519

AT7519 (AT7519M) is a potent inhibitor of CDKs, with IC50s of 210, 47, 100, 13, 170, and 10 nM for CDK1, CDK2, CDK4 to CDK6, and CDK9, respectively. AT7519 shows encouraging anticancer activity against multiple cancer cell lines and tumor xenografts,. AT7519 has also been evaluated in several clinical trials, including lymphoma and unspecified adult solid tumors, multiple myeloma, and leukemia. A phase 1 study of AT7519 was conducted to evaluate the safety and tolerability. The preliminary anticancer activity was observed with AT7519 at 27.0 mg/m2. Additionally, promising preliminary clinical activity was observed when AT7519 was combined with the HSP90 inhibitor onalespib. Collectively, AT7519 is also another promising CDK1-associated inhibitor for cancer treatment in the clinic.

Other CDK1 inhibitors

Seliciclib (Roscovitine), AG-024322, PHA-793887, R547, RGB-286638, AZD-5438, and Indirubin (Couroupitine B) exhibited potential for clinical application (Supplementary Table 5). However, assessment of the safety and antitumor activity is still needed in future studies.

Limitation and potential of targeting CDK1

CDK1-associated inhibitors might replace traditional endocrine therapies in many situations. However, adverse side effects, and less efficacy– are still limitations for clinical application. Because CDKs play important roles in normal cellular processes, targeting them can lead to unintended consequences, such as toxicity and other adverse effects. Comprehensively understanding the mechanisms by which CDKs contribute to cancer and normal cell functions is crucial to balance the potential benefits of CDK inhibitors with their risks and toxicities. Designing CDK inhibitors that selectively target cancer cells while minimizing toxicity to normal cells requires intricate knowledge of CDK regulation. To address the limitations of CDK inhibitors, combination treatment with other anti-cancer agents might be best use in cancer treatment. Highlighting the distinct regulatory mechanisms of CDK1 activity in different cancer types can enhance precision oncology and enable successful combinatorial treatment with CDK1 inhibitors–. For instance, CDK1 inhibition can be a potential therapy for MYC-dependent breast cancer. In the clinical application, the toxicities are manageable and clinical activity was observed when flavopiridol in combination with paclitaxel in patients with esophagus, lung, and prostate cancer. The pan-CDK1 inhibitor dinaciclib in combination with rituximab, an anti-CD20 monoclonal antibody, was well tolerated and revealed encouraging clinical activity in relapsed/refractory chronic lymphocytic leukemia patients. In addition, promising preliminary clinical activity has been observed in a Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advanced solid tumors. Furthermore, several clinical trials of CDK1 associated inhibitors combining with other anti-cancer agents are ongoing to evaluate the combination treatment in cancer (NCT03579836; NCT03484520; NCT01434316; NCT01676753). These clinical studies will provide more information for the combination of CDK1 associated inhibitors with other anti-cancer agents for cancer treatment.

Besides side effects, several clinical trials indicated that CDK1-associated inhibitors failed to demonstrate sufficient efficacy in cancer patients–. The preclinical data suggest that the lack of efficacy of CDK1 associated inhibitors might be associated with poor pharmacokinetics of the drugs,. In addition, clinical trials performed on some cancer patients failed to respond to treatment because of low expression levels of CDK1. Another possible reason for the lack of efficacy could be related to advanced stage of tumor progression enabling more resistance to therapy in general. To improve these issues, screening of patients with high CDK1 expression is important for recruiting patients. Additionally, combination therapy should also be an effective approach to enhance the efficacy of CDK1-associated inhibitors in clinical trials.

Summary

In this review, we focused on the role the CDK1 in cancer and examined the potential application of targeting CDK1 for cancer treatment. We demonstrated the expression level and associated survival rate of CDKs in multiple cancer types. The results suggest that CDK1 is a promising target protein in various cancers. We also examined proteins that interact and mediate CDK1 or are mediated by CDK1. Our analysis demonstrated that CDK1-associated proteins play a critical role in multiple cancer signaling pathways. These results provide evidence of clinical benefits of CKIs. A series of preclinical studies have shown that CKIs mediate various cancer cell processes including proliferation, apoptosis, invasion, and metastasis. Importantly, several preclinical animal studies and clinical studies demonstrated the efficacy of CKIs in cancer treatment. These results are summarized in Fig. 4 and suggest potential opportunities for targeting CDK1 as a cancer treatment.

Overall, this review summarized the function and mechanism of CDK1 in cancer. Targeting CDK1 might provide opportunities for cancer prevention and therapy. The combined CDK1 associated inhibitors with other anticancer agents might improve the chemotherapeutic benefits and improve clinical outcome in cancer development. Future studies are required to determine these issues–.

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  92. 92.

    Tanguay P-L, Rodier G, Meloche S. C-terminal domain phosphorylation of ERK3 controlled by Cdk1 and Cdc14 regulates its stability in mitosis. Biochem. J. 2010;428:103-111.

    Not in our library10.1042/bj20091604 (opens in a new tab)

  93. 93.

    Gao, X. et al. Phosphorylation of the androgen receptor at Ser81 is co‐sustained by CDK1 and CDK9 and leads to AR‐mediated transactivation in prostate cancer. Mol. Oncol.15, 1901–1920 (2021).

    Not in our library10.1002/1878-0261.12968 (opens in a new tab)

  94. 94.

    Chen S, Xu Y, Yuan X, Bubley GJ, Balk SP. Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proc. Natl Acad. Sci. 2006;103:15969-15974.

    Not in our library10.1073/pnas.0604193103 (opens in a new tab)

  95. 95.

    Willder J, et al. Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients. Br. J. Cancer. 2013;108:139-148.

    Not in our library10.1038/bjc.2012.480 (opens in a new tab)

  96. 96.

    Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Science’s STKE. 2005;2005:re12-re12.

    Not in our library10.1126/stke.3062005re12 (opens in a new tab)

  97. 97.

    Rankin Eá, Giaccia A. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 2008;15:678-685.

    Not in our library10.1038/cdd.2008.21 (opens in a new tab)

  98. 98.

    Warfel NA, Dolloff NG, Dicker DT, Malysz J, El-Deiry WS. CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth. Cell Cycle. 2013;12:3689-3701.

    Not in our library10.4161/cc.26930 (opens in a new tab)

  99. 99.

    Yang S, et al. CDK1 phosphorylation of YAP promotes mitotic defects and cell motility and is essential for neoplastic transformation. Cancer Res. 2013;73:6722-6733.

    Not in our library10.1158/0008-5472.can-13-2049 (opens in a new tab)

  100. 100.

    Zhang L, et al. CDK1 phosphorylation of TAZ in mitosis inhibits its oncogenic activity. Oncotarget. 2015;6:31399.

    Not in our library10.18632/oncotarget.5189 (opens in a new tab)

  101. 101.

    Chen X, Stauffer S, Chen Y, Dong J. Ajuba phosphorylation by CDK1 promotes cell proliferation and tumorigenesis. J. Biol. Chem. 2016;291:14761-14772.

    Not in our library10.1074/jbc.m116.722751 (opens in a new tab)

  102. 102.

    Major ML, Lepe R, Costa RH. Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Mol. Cell. Biol. 2004;24:2649-2661.

    Not in our library10.1128/mcb.24.7.2649-2661.2004 (opens in a new tab)

  103. 103.

    Shi Q, et al. Phosphorylation of islet-1 serine 269 by CDK1 increases its transcriptional activity and promotes cell proliferation in gastric cancer. Mol. Med. 2021;27:1-11.

    Not in our library10.1186/s10020-021-00302-6 (opens in a new tab)

  104. 104.

    Velásquez C, et al. Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation. Proc. Natl Acad. Sci. 2016;113:8466-8471.

    Not in our library10.1073/pnas.1607768113 (opens in a new tab)

  105. 105.

    Eferl R, Wagner EF. AP-1: a double-edged sword in tumorigenesis. Nat. Rev. Cancer. 2003;3:859-868.

    Not in our library10.1038/nrc1209 (opens in a new tab)

  106. 106.

    Hasegawa H, et al. Cdk1-mediated phosphorylation of human ATF7 at Thr-51 and Thr-53 promotes cell-cycle progression into M phase. PLoS ONE. 2014;9:e116048.

    Not in our library10.1371/journal.pone.0116048 (opens in a new tab)

  107. 107.

    Guo H, Friedman AD. Phosphorylation of RUNX1 by cyclin-dependent kinase reduces direct interaction with HDAC1 and HDAC3. J. Biol. Chem. 2011;286:208-215.

    Not in our library10.1074/jbc.m110.149013 (opens in a new tab)

  108. 108.

    Qiao M, et al. Cell cycle-dependent phosphorylation of the RUNX2 transcription factor by cdc2 regulates endothelial cell proliferation. J. Biol. Chem. 2006;281:7118-7128.

    Not in our library10.1074/jbc.m508162200 (opens in a new tab)

  109. 109.

    Adam-Stitah S, Penna L, Chambon P, Rochette-Egly C. Hyperphosphorylation of the retinoid X receptor α by activated c-Jun NH2-terminal kinases. J. Biol. Chem. 1999;274:18932-18941.

    Not in our library10.1074/jbc.274.27.18932 (opens in a new tab)

  110. 110.

    Radomska HS, et al. Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBPα. J. Clin. Investig. 2012;122:2955-2966.

    Not in our library10.1172/jci43354 (opens in a new tab)

  111. 111.

    Heo J, et al. Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis. EMBO Mol. Med. 2020;12:e10880.

    Not in our library10.15252/emmm.201910880 (opens in a new tab)

  112. 112.

    Wang Y-D, et al. OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway. Cell Death Dis. 2013;4:e760-e760.

    Not in our library10.1038/cddis.2013.272 (opens in a new tab)

  113. 113.

    Kim HJ, et al. Cyclin-dependent kinase 1 activity coordinates the chromatin associated state of Oct4 during cell cycle in embryonic stem cells. Nucleic Acids Res. 2018;46:6544-6560.

    Not in our library10.1093/nar/gky371 (opens in a new tab)

  114. 114.

    Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol. Cell. Biol. 2010;30:640-656.

    Not in our library10.1128/mcb.00882-09 (opens in a new tab)

  115. 115.

    Sakurikar N, Eichhorn JM, Chambers TC. Cyclin-dependent kinase-1 (Cdk1)/cyclin B1 dictates cell fate after mitotic arrest via phosphoregulation of antiapoptotic Bcl-2 proteins. J. Biol. Chem. 2012;287:39193-39204.

    Not in our library10.1074/jbc.m112.391854 (opens in a new tab)

  116. 116.

    Choi HJ, Zhu BT. Role of cyclin B1/Cdc2 in mediating Bcl‐XL phosphorylation and apoptotic cell death following nocodazole‐induced mitotic arrest. Mol. Carcinogenesis. 2014;53:125-137.

    Not in our library10.1002/mc.21956 (opens in a new tab)

  117. 117.

    LeBlanc FR, et al. Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia. Cancer Biol. Ther. 2015;16:1830-1840.

    Not in our library10.1080/15384047.2015.1078949 (opens in a new tab)

  118. 118.

    Darweesh, O. et al. Identification of a novel Bax–Cdk1 signalling complex that links activation of the mitotic checkpoint to apoptosis. J. Cell Sci.134 (2021).

    Not in our library10.1242/jcs.244152 (opens in a new tab)

  119. 119.

    Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J. Biol. Chem. 2007;282:11521-11529.

    Not in our library10.1074/jbc.m607279200 (opens in a new tab)

  120. 120.

    Zaja I, et al. Cdk1, PKCδ and calcineurin-mediated Drp1 pathway contributes to mitochondrial fission-induced cardiomyocyte death. Biochem. Biophys. Res. Commun. 2014;453:710-721.

    Not in our library10.1016/j.bbrc.2014.09.144 (opens in a new tab)

  121. 121.

    Tailor D, Hahm E-R, Kale RK, Singh SV, Singh RP. Sodium butyrate induces DRP1-mediated mitochondrial fusion and apoptosis in human colorectal cancer cells. Mitochondrion. 2014;16:55-64.

    Not in our library10.1016/j.mito.2013.10.004 (opens in a new tab)

  122. 122.

    Cepeda D, et al. CDK‐mediated activation of the SCFFBXO 28 ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancer. EMBO Mol. Med. 2013;5:1067-1086.

    Not in our library10.1002/emmm.201202341 (opens in a new tab)

  123. 123.

    Nakajima T, et al. Regulation of GATA-binding protein 2 levels via ubiquitin-dependent degradation by Fbw7: involvement of cyclin B-cyclin-dependent kinase 1-mediated phosphorylation of THR176 in GATA-binding protein 2. J. Biol. Chem. 2015;290:10368-10381.

    Not in our library10.1074/jbc.m114.613018 (opens in a new tab)

  124. 124.

    Bunz F, et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science. 1998;282:1497-1501.

    Not in our library10.1126/science.282.5393.1497 (opens in a new tab)

  125. 125.

    Nantajit D, et al. Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response. PLoS ONE. 2010;5:e12341.

    Not in our library10.1371/journal.pone.0012341 (opens in a new tab)

  126. 126.

    Gaiddon C, et al. Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73. J. Biol. Chem. 2003;278:27421-27431.

    Not in our library10.1074/jbc.m300251200 (opens in a new tab)

  127. 127.

    Yuan Z, et al. Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science. 2008;319:1665-1668.

    Not in our library10.1126/science.1152337 (opens in a new tab)

  128. 128.

    Liu P, Kao T, Huang H. CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene. 2008;27:4733-4744.

    Not in our library10.1038/onc.2008.104 (opens in a new tab)

  129. 129.

    Matthess Y, Raab M, Sanhaji M, Lavrik IN, Strebhardt K. Cdk1/cyclin B1 controls Fas-mediated apoptosis by regulating caspase-8 activity. Mol. Cell. Biol. 2010;30:5726-5740.

    Not in our library10.1128/mcb.00731-10 (opens in a new tab)

  130. 130.

    Allan LA, Clarke PR. Phosphorylation of caspase-9 by CDK1/cyclin B1 protects mitotic cells against apoptosis. Mol. Cell. 2007;26:301-310.

    Not in our library10.1016/j.molcel.2007.03.019 (opens in a new tab)

  131. 131.

    Narayan N, Massimi P, Banks L. CDK phosphorylation of the discs large tumour suppressor controls its localisation and stability. J. Cell Sci. 2009;122:65-74.

    Not in our library10.1242/jcs.024554 (opens in a new tab)

  132. 132.

    Margottin-Goguet F, et al. Prophase destruction of Emi1 by the SCFβTrCP/Slimb ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Dev. Cell. 2003;4:813-826.

    Not in our library10.1016/s1534-5807(03)00153-9 (opens in a new tab)

  133. 133.

    Linares JF, Amanchy R, Diaz-Meco MT, Moscat J. Phosphorylation of p62 by cdk1 controls the timely transit of cells through mitosis and tumor cell proliferation. Mol. Cell. Biol. 2011;31:105-117.

    Not in our library10.1128/mcb.00620-10 (opens in a new tab)

  134. 134.

    Miao H, et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat. Cell Biol. 2001;3:527-530.

    Not in our library10.1038/35074604 (opens in a new tab)

  135. 135.

    Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. Ligation of EphA2 by Ephrin A1-Fc inhibits pancreatic adenocarcinoma cellular invasiveness. Biochem. Biophys. Res. Commun. 2004;320:1096-1102.

    Not in our library10.1016/j.bbrc.2004.06.054 (opens in a new tab)

  136. 136.

    Zeng Y, et al. Cyclin-dependent kinase 1 (CDK1)-mediated mitotic phosphorylation of the transcriptional co-repressor Vgll4 inhibits its tumor-suppressing activity. J. Biol. Chem. 2017;292:15028-15038.

    Not in our library10.1074/jbc.m117.796284 (opens in a new tab)

  137. 137.

    Cho HJ, et al. Cdk1 protein-mediated phosphorylation of receptor-associated protein 80 (RAP80) serine 677 modulates DNA damage-induced G2/M checkpoint and cell survival. J. Biol. Chem. 2013;288:3768-3776.

    Not in our library10.1074/jbc.m112.401299 (opens in a new tab)

  138. 138.

    Schwarz MA, Thornton J, Xu H, Awasthi N, Schwarz RE. Cell proliferation and migration are modulated by Cdk-1-phosphorylated endothelial-monocyte activating polypeptide II. PLoS ONE. 2012;7:e33101.

    Not in our library10.1371/journal.pone.0033101 (opens in a new tab)

  139. 139.

    Fung, T. K. & Poon, R. Y. Semin. Cell Dev. Biol.16, 335–342 (Elsevier).

    Not in our library10.1016/j.semcdb.2005.02.014 (opens in a new tab)

  140. 140.

    Thomas Y, et al. Cdk1 phosphorylates SPAT-1/Bora to promote Plk1 activation in C. elegans and human cells. Cell Rep. 2016;15:510-518.

    Not in our library10.1016/j.celrep.2016.03.049 (opens in a new tab)

  141. 141.

    Liu J, Wang XN, Cheng F, Liou Y-C, Deng L-W. Phosphorylation of mixed lineage leukemia 5 by CDC2 affects its cellular distribution and is required for mitotic entry. J. Biol. Chem. 2010;285:20904-20914.

    Not in our library10.1074/jbc.m109.098558 (opens in a new tab)

  142. 142.

    Blake-Hodek KA, et al. Determinants for activation of the atypical AGC kinase Greatwall during M phase entry. Mol. Cell. Biol. 2012;32:1337-1353.

    Not in our library10.1128/mcb.06525-11 (opens in a new tab)

  143. 143.

    Rodriguez-Rodriguez J-A, Moyano Y, Játiva S, Queralt E. Mitotic exit function of Polo-like kinase Cdc5 is dependent on sequential activation by Cdk1. Cell Rep. 2016;15:2050-2062.

    Not in our library10.1016/j.celrep.2016.04.079 (opens in a new tab)

  144. 144.

    Yu Z, et al. Dynamic phosphorylation of CENP-A at Ser68 orchestrates its cell-cycle-dependent deposition at centromeres. Dev. Cell. 2015;32:68-81.

    Not in our library10.1016/j.devcel.2014.11.030 (opens in a new tab)

  145. 145.

    Abe S, et al. The initial phase of chromosome condensation requires Cdk1-mediated phosphorylation of the CAP-D3 subunit of condensin II. Genes Dev. 2011;25:863-874.

    Not in our library10.1101/gad.2016411 (opens in a new tab)

  146. 146.

    Diani L, et al. Saccharomyces CDK1 phosphorylates Rad53 kinase in metaphase, influencing cellular morphogenesis. J. Biol. Chem. 2009;284:32627-32634.

    Not in our library10.1074/jbc.m109.048157 (opens in a new tab)

  147. 147.

    Daum JR, et al. Ska3 is required for spindle checkpoint silencing and the maintenance of chromosome cohesion in mitosis. Curr. Biol. 2009;19:1467-1472.

    Not in our library10.1016/j.cub.2009.07.017 (opens in a new tab)

  148. 148.

    Zhang Q, et al. Ska3 phosphorylated by Cdk1 binds Ndc80 and recruits Ska to kinetochores to promote mitotic progression. Curr. Biol. 2017;27:1477-1484.e1474.

    Not in our library10.1016/j.cub.2017.03.060 (opens in a new tab)

  149. 149.

    Busti S, et al. Overexpression of Far1, a cyclin-dependent kinase inhibitor, induces a large transcriptional reprogramming in which RNA synthesis senses Far1 in a Sfp1-mediated way. Biotechnol. Adv. 2012;30:185-201.

    Not in our library10.1016/j.biotechadv.2011.09.007 (opens in a new tab)

  150. 150.
    CDK1 phosphorylates WRN at collapsed replication forks · 2016
    Not checked
  151. 151.

    Knockleby J, Kim BJ, Mehta A, Lee H. Cdk1-mediated phosphorylation of Cdc7 suppresses DNA re-replication. Cell Cycle. 2016;15:1494-1505.

    Not in our library10.1080/15384101.2016.1176658 (opens in a new tab)

  152. 152.

    Johnson N, et al. Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage. Mol. Cell. 2009;35:327-339.

    Not in our library10.1016/j.molcel.2009.06.036 (opens in a new tab)

  153. 153.

    Granata M, et al. Dynamics of Rad9 chromatin binding and checkpoint function are mediated by its dimerization and are cell cycle–regulated by CDK1 activity. PLoS Genet. 2010;6:e1001047.

    Not in our library10.1371/journal.pgen.1001047 (opens in a new tab)

  154. 154.

    McKerlie M, Walker JR, Mitchell TR, Wilson FR, Zhu X-D. Phosphorylated (pT371) TRF1 is recruited to sites of DNA damage to facilitate homologous recombination and checkpoint activation. Nucleic Acids Res. 2013;41:10268-10282.

    Not in our library10.1093/nar/gkt775 (opens in a new tab)

  155. 155.

    Kim HH, et al. Nuclear HuR accumulation through phosphorylation by Cdk1. Genes Dev. 2008;22:1804-1815.

    Not in our library10.1101/gad.1645808 (opens in a new tab)

  156. 156.
    Metascape provides a biologist-oriented resource for the analysis of systems-level datasets · 2019
    No notice
  157. 157.

    Vassilev LT, et al. Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1. Proc. Natl Acad. Sci. 2006;103:10660-10665.

    Not in our library10.1073/pnas.0600447103 (opens in a new tab)

  158. 158.

    Schwermer M, et al. Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors. Oncotarget. 2015;6:15425.

    Not in our library10.18632/oncotarget.3908 (opens in a new tab)

  159. 159.

    Wu CX, et al. Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma. Theranostics. 2018;8:3737.

    Not in our library10.7150/thno.25487 (opens in a new tab)

  160. 160.

    Park S, et al. CGP74514A enhances TRAIL-induced apoptosis in breast cancer cells by reducing X-linked inhibitor of apoptosis protein. Anticancer Res. 2014;34:3557-3562.

    Not in our library

  161. 161.

    Larsson DE, et al. Identification and evaluation of potential anti-cancer drugs on human neuroendocrine tumor cell lines. Anticancer Res. 2006;26:4125-4129.

    Not in our library

  162. 162.

    Seufferlein, T., Kestler, A., Beutel, A., Perkhofer, L. & Ettrich, T. Translational Pancreatic Cancer Research 219–232 (Springer, 2020).

    Not in our library

  163. 163.

    Bose P, Vachhani P, Cortes JE. Treatment of relapsed/refractory acute myeloid leukemia. Curr. Treat. Options Oncol. 2017;18:17.

    Not in our library10.1007/s11864-017-0456-2 (opens in a new tab)

  164. 164.

    Hofmeister CC, et al. A phase I trial of flavopiridol in relapsed multiple myeloma. Cancer Chemother. Pharmacol. 2014;73:249-257.

    Not in our library10.1007/s00280-013-2347-y (opens in a new tab)

  165. 165.

    Bose P, Grant S. Orphan drug designation for pracinostat, volasertib and alvocidib in AML. Leuk. Res. 2014;38:862-865.

    Not in our library10.1016/j.leukres.2014.06.007 (opens in a new tab)

  166. 166.

    Shapiro GI, Koestner DA, Matranga CB, Rollins BJ. Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines. Clin. Cancer Res. 1999;5:2925-2938.

    Not in our library

  167. 167.

    Motwani M, et al. Augmentation of apoptosis and tumor regression by flavopiridol in the presence of CPT-11 in Hct116 colon cancer monolayers and xenografts. Clin. Cancer Res. 2001;7:4209-4219.

    Not in our library

  168. 168.

    Aklilu M, Kindler H, Donehower R, Mani S, Vokes E. Phase II study of flavopiridol in patients with advanced colorectal cancer. Ann. Oncol. 2003;14:1270-1273.

    Not in our library10.1093/annonc/mdg343 (opens in a new tab)

  169. 169.

    Schwartz GK, et al. Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J. Clin. Oncol. 2002;20:2157-2170.

    Not in our library10.1200/jco.2002.08.080 (opens in a new tab)

  170. 170.

    Bahleda R, et al. Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies. Br. J. Cancer. 2017;116:1505-1512.

    Not in our library10.1038/bjc.2017.92 (opens in a new tab)

  171. 171.

    Cho BC, et al. Phase Ib/II study of the pan-cyclin-dependent kinase inhibitor roniciclib in combination with chemotherapy in patients with extensive-disease small-cell lung cancer. Lung Cancer. 2018;123:14-21.

    Not in our library10.1016/j.lungcan.2018.04.022 (opens in a new tab)

  172. 172.

    Reck M, et al. Phase II study of roniciclib in combination with cisplatin/etoposide or carboplatin/etoposide as first-line therapy in patients with extensive-disease small cell lung cancer. J. Thorac. Oncol. 2019;14:701-711.

    Not in our library10.1016/j.jtho.2019.01.010 (opens in a new tab)

  173. 173.

    Hirte, H. et al. A phase 1 study of selective cyclin dependent kinase inhibitor P276-00 in patients with advanced refractory neoplasms. Cancer Res. 67, 4368 (2007).

    Not in our library

  174. 174.

    Stone, A., Sutherland, R. L. & Musgrove, E. A. Inhibitors of cell cycle kinases: recent advances and future prospects as cancer therapeutics. Crit. Rev. Oncogenesis17 (2012).

    Not in our library10.1615/critrevoncog.v17.i2.40 (opens in a new tab)

  175. 175.

    Cassaday RD, et al. A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Clin. Lymphoma Myeloma Leuk. 2015;15:392-397.

    Not in our library10.1016/j.clml.2015.02.021 (opens in a new tab)

  176. 176.

    Flynn J, et al. Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. Leukemia. 2015;29:1524-1529.

    Not in our library10.1038/leu.2015.31 (opens in a new tab)

  177. 177.

    Kumar SK, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood, J. Am. Soc. Hematol. 2015;125:443-448.

    Not in our library10.1182/blood-2014-05-573741 (opens in a new tab)

  178. 178.

    Mita MM, et al. Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. Clin. Breast Cancer. 2014;14:169-176.

    Not in our library10.1016/j.clbc.2013.10.016 (opens in a new tab)

  179. 179.

    Squires MS, et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol. Cancer Therapeutics. 2009;8:324-332.

    Not in our library10.1158/1535-7163.mct-08-0890 (opens in a new tab)

  180. 180.

    Squires MS, et al. AT7519, a cyclin-dependent kinase inhibitor, exerts its effects by transcriptional inhibition in leukemia cell lines and patient samples. Mol. Cancer Therapeutics. 2010;9:920-928.

    Not in our library10.1158/1535-7163.mct-09-1071 (opens in a new tab)

  181. 181.

    Chen E, et al. A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177. Br. J. Cancer. 2014;111:2262-2267.

    Not in our library10.1038/bjc.2014.565 (opens in a new tab)

  182. 182.

    Do KT, et al. Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 2020;86:815-827.

    Not in our library10.1007/s00280-020-04176-z (opens in a new tab)

  183. 183.

    Phelps MA, et al. Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood, J. Am. Soc. Hematol. 2009;113:2637-2645.

    Not in our library10.1182/blood-2008-07-168583 (opens in a new tab)

  184. 184.

    Lin TS, et al. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J. Clin. Oncol. 2009;27:6012.

    Not in our library10.1200/jco.2009.22.6944 (opens in a new tab)

  185. 185.

    Gregory, G. et al. Antitumor activity of pembrolizumab plus dinaciclib in patients with diffuse large B cell lymphoma: the phase 1B Keynote-155 study (2019).

    Not in our library10.1182/bloodadvances.2021005872 (opens in a new tab)

  186. 186.

    Stephenson JJ, et al. Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer. Lung Cancer. 2014;83:219-223.

    Not in our library10.1016/j.lungcan.2013.11.020 (opens in a new tab)

  187. 187.

    Morris DG, et al. A phase II study of flavopiridol in patients with previously untreated advanced soft tissue sarcoma. Sarcoma. 2006;2006:64374.

    Not in our library10.1155/srcm/2006/64374 (opens in a new tab)

  188. 188.
    Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells · 2014
    No notice
  189. 189.

    Xia Q, et al. The CDK1 inhibitor RO3306 improves the response of BRCA-proficient breast cancer cells to PARP inhibition. Int. J. Oncol. 2014;44:735-744.

    Not in our library10.3892/ijo.2013.2240 (opens in a new tab)

  190. 190.
    Targeting Cyclin-Dependent Kinases for Treatment of Gynecologic Cancers · 2018
    Not checked
  191. 191.

    Fabre C, et al. Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients. Cancer Chemother. Pharmacol. 2014;74:1057-1064.

    Not in our library10.1007/s00280-014-2583-9 (opens in a new tab)

  192. 192.

    Mita MM, et al. Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies. Br. J. Cancer. 2017;117:1258-1268.

    Not in our library10.1038/bjc.2017.288 (opens in a new tab)

  193. 193.

    Nemunaitis JJ, et al. A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies. J. Transl. Med. 2013;11:1-14.

    Not in our library10.1186/1479-5876-11-259 (opens in a new tab)

  194. 194.

    Sasayama T, et al. Over‐expression of Aurora‐A targets cytoplasmic polyadenylation element binding protein and promotes mRNA polyadenylation of Cdk1 and cyclin B1. Genes Cells. 2005;10:627-638.

    Not in our library10.1111/j.1365-2443.2005.00870.x (opens in a new tab)

  195. 195.

    Chen J, et al. Ribosomal protein S15A promotes malignant transformation and predicts poor outcome in colorectal cancer through misregulation of p53 signaling pathway. Int. J. Oncol. 2016;48:1628-1638.

    Not in our library10.3892/ijo.2016.3366 (opens in a new tab)

  196. 196.

    Zhang B, et al. TPX2 mediates prostate cancer epithelial-mesenchymal transition through CDK1 regulated phosphorylation of ERK/GSK3β/SNAIL pathway. Biochem. Biophys. Res. Commun. 2021;546:1-6.

    Not in our library10.1016/j.bbrc.2021.01.106 (opens in a new tab)

  197. 197.

    Yang Y, et al. c-Myc regulates the CDK1/cyclin B1 dependent‑G2/M cell cycle progression by histone H4 acetylation in Raji cells Corrigendum in/10.3892/ijmm. 2019.4318. Int. J. Mol. Med. 2018;41:3366-3378.

    Not in our library10.3892/ijmm.2018.3519 (opens in a new tab)

  198. 198.

    Maimaiti A, Aizezi A, Anniwaer J. Zinc finger of the cerebellum 5 promotes colorectal cancer cell proliferation and cell cycle progression through enhanced CDK1/CDC25c signaling. Arch. Med. Sci.: AMS. 2021;17:449.

    Not in our library10.5114/aoms.2019.89677 (opens in a new tab)

  199. 199.

    Gao CL, Wang GW, Yang GQ, Yang H, Zhuang L. Karyopherin subunit-α 2 expression accelerates cell cycle progression by upregulating CCNB2 and CDK1 in hepatocellular carcinoma. Oncol. Lett. 2018;15:2815-2820.

    Not in our library10.3892/ol.2017.7691 (opens in a new tab)

  200. 200.

    Li Q, Wang W, Hu Y-C, Yin T-T, He J. Knockdown of ubiquitin associated protein 2-like (UBAP2L) inhibits growth and metastasis of hepatocellular carcinoma. Med. Sci. Monit.: Int. Med. J. Exp. Clin. Res. 2018;24:7109.

    Not in our library10.12659/msm.912861 (opens in a new tab)

  201. 201.

    Zhang X, Pan Y, Fu H, Zhang J. Nucleolar and spindle associated protein 1 (NUSAP1) inhibits cell proliferation and enhances susceptibility to epirubicin in invasive breast cancer cells by regulating cyclin D kinase (CDK1) and DLGAP5 expression. Med. Sci. Monit.: Int. Med. J. Exp. Clin. Res. 2018;24:8553.

    Not in our library10.12659/msm.910364 (opens in a new tab)

  202. 202.

    Jang Y-J, Ma S, Terada Y, Erikson RL. Phosphorylation of threonine 210 and the role of serine 137 in the regulation of mammalian polo-like kinase. J. Biol. Chem. 2002;277:44115-44120.

    Not in our library10.1074/jbc.m202172200 (opens in a new tab)

  203. 203.

    Ito Y, et al. Polo-like kinase 1 (PLK1) expression is associated with cell proliferative activity and cdc2 expression in malignant lymphoma of the thyroid. Anticancer Res. 2004;24:259-264.

    Not in our library

  204. 204.

    Liu, W., Zhang, R., Li, E., Wu, L. & Wang, J. IFITM3 regulates NCAPG through phosphorylation to influence the invasion and metastasis of HCC. 10.21203/rs.3.rs-54017/v1 (2020).

    Not in our library

  205. 205.

    Yi X, Li Y, Zai H, Long X, Li W. KLF8 knockdown triggered growth inhibition and induced cell phase arrest in human pancreatic cancer cells. Gene. 2016;585:22-27.

    Not in our library10.1016/j.gene.2016.03.025 (opens in a new tab)

  206. 206.

    Boufraqech M, et al. LOX is a novel mitotic spindle-associated protein essential for mitosis. Oncotarget. 2016;7:29023.

    Not in our library10.18632/oncotarget.8628 (opens in a new tab)

  207. 207.

    Qu G-q, et al. Effect of RTKN on progression and metastasis of colon cancer in vitro. Biomedicine Pharmacother. 2015;74:117-123.

    Not in our library10.1016/j.biopha.2015.07.012 (opens in a new tab)

  208. 208.

    Ishitsuka Y, et al. Pituitary tumor-transforming gene 1 enhances proliferation and suppresses early differentiation of keratinocytes. J. investigative Dermatol. 2012;132:1775-1784.

    Not in our library10.1038/jid.2012.74 (opens in a new tab)

  209. 209.

    Galarreta, A. et al. USP7 limits CDK1 activity throughout the cell cycle. EMBO J.40, e99692 (2021).

    Not in our library10.15252/embj.201899692 (opens in a new tab)

  210. 210.

    Chiu H-C, et al. Suppression of vimentin phosphorylation by the avian reovirus p17 through inhibition of CDK1 and Plk1 impacting the G2/M phase of the cell cycle. PLoS ONE. 2016;11:e0162356.

    Not in our library10.1371/journal.pone.0162356 (opens in a new tab)

  211. 211.

    Hsieh WL, et al. IFI27, a novel epidermal growth factor‐stabilized protein, is functionally involved in proliferation and cell cycling of human epidermal keratinocytes. Cell Prolif. 2015;48:187-197.

    Not in our library10.1111/cpr.12168 (opens in a new tab)

  212. 212.

    Nalepa G, et al. The tumor suppressor CDKN3 controls mitosis. J. Cell Biol. 2013;201:997-1012.

    Not in our library10.1083/jcb.201205125 (opens in a new tab)

  213. 213.

    Park S-Y, et al. Depletion of BubR1 promotes premature centrosomal localization of cyclin B1 and accelerates mitotic entry. Cell Cycle. 2009;8:1754-1764.

    Not in our library10.4161/cc.8.11.8671 (opens in a new tab)

  214. 214.

    Liu W, Li W, Fujita T, Yang Q, Wan Y. Proteolysis of CDH1 enhances susceptibility to UV radiation-induced apoptosis. Carcinogenesis. 2008;29:263-272.

    Not in our library10.1093/carcin/bgm251 (opens in a new tab)

  215. 215.

    Yde C, Olsen B, Meek D, Watanabe N, Guerra B. The regulatory β-subunit of protein kinase CK2 regulates cell-cycle progression at the onset of mitosis. Oncogene. 2008;27:4986-4997.

    Not in our library10.1038/onc.2008.146 (opens in a new tab)

  216. 216.

    LaGory EL, Sitailo LA, Denning MF. The protein kinase Cδ catalytic fragment is critical for maintenance of the G2/M DNA damage checkpoint. J. Biol. Chem. 2010;285:1879-1887.

    Not in our library10.1074/jbc.m109.055392 (opens in a new tab)

  217. 217.

    Ovejero-Benito MC, Frade JM. Brain-derived neurotrophic factor-dependent cdk1 inhibition prevents G2/M progression in differentiating tetraploid neurons. PLoS ONE. 2013;8:e64890.

    Not in our library10.1371/journal.pone.0064890 (opens in a new tab)

  218. 218.

    Schmidt A-K, et al. The p53/p73-p21 CIP1 tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells. Oncogene. 2021;40:436-451.

    Not in our library10.1038/s41388-020-01524-4 (opens in a new tab)

  219. 219.

    Satyanarayana A, Hilton MB, Kaldis P. p21 Inhibits Cdk1 in the absence of Cdk2 to maintain the G1/S phase DNA damage checkpoint. Mol. Biol. Cell. 2008;19:65-77.

    Not in our library10.1091/mbc.e07-06-0525 (opens in a new tab)

  220. 220.

    Carujo S, et al. Glyceraldehyde 3-phosphate dehydrogenase is a SET-binding protein and regulates cyclin B-cdk1 activity. Oncogene. 2006;25:4033-4042.

    Not in our library10.1038/sj.onc.1209433 (opens in a new tab)

  221. 221.

    Canela N, et al. The SET protein regulates G2/M transition by modulating cyclin B-cyclin-dependent kinase 1 activity. J. Biol. Chem. 2003;278:1158-1164.

    Not in our library10.1074/jbc.m207497200 (opens in a new tab)

  222. 222.
    NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor · 2019
    Not checked
  223. 223.

    Paruthiyil S, et al. Estrogen receptor β causes a G2 cell cycle arrest by inhibiting CDK1 activity through the regulation of cyclin B1, GADD45A, and BTG2. Breast Cancer Res. Treat. 2011;129:777-784.

    Not in our library10.1007/s10549-010-1273-5 (opens in a new tab)

  224. 224.

    Toyo-oka K, et al. Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation. J. Cell Biol. 2008;180:1133-1147.

    Not in our library10.1083/jcb.200705148 (opens in a new tab)

  225. 225.

    Buffone MG, Schindler K, Schultz RM. Over-expression of CDC14B causes mitotic arrest and inhibits zygotic genome activation in mouse preimplantation embryos. Cell Cycle. 2009;8:3904-3913.

    Not in our library10.4161/cc.8.23.10074 (opens in a new tab)

  226. 226.

    Majdzadeh N, et al. HDAC4 inhibits cell‐cycle progression and protects neurons from cell death. Dev. Neurobiol. 2008;68:1076-1092.

    Not in our library10.1002/dneu.20637 (opens in a new tab)

  227. 227.

    Ullah Z, Kohn MJ, Yagi R, Vassilev LT, DePamphilis ML. Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity. Genes Dev. 2008;22:3024-3036.

    Not in our library10.1101/gad.1718108 (opens in a new tab)

  228. 228.

    Xiao Y, Lucas B, Molcho E, Schiff T, Vigodner M. Inhibition of CDK1 activity by sumoylation. Biochem. Biophys. Res. Commun. 2016;478:919-923.

    Not in our library10.1016/j.bbrc.2016.08.051 (opens in a new tab)

  229. 229.

    Tran T, Kolupaeva V, Basilico C. FGF inhibits the activity of the cyclin B1/CDK1 kinase to induce a transient G2 arrest in RCS chondrocytes. Cell Cycle. 2010;9:4379-4386.

    Not in our library10.4161/cc.9.21.13671 (opens in a new tab)

  230. 230.

    Yim H, Erikson RL. Cell division cycle 6, a mitotic substrate of polo-like kinase 1, regulates chromosomal segregation mediated by cyclin-dependent kinase 1 and separase. Proc. Natl Acad. Sci. 2010;107:19742-19747.

    Not in our library10.1073/pnas.1013557107 (opens in a new tab)

  231. 231.

    Sabour Alaoui S, et al. TWEAK affects keratinocyte G2/M growth arrest and induces apoptosis through the translocation of the AIF protein to the nucleus. PLoS ONE. 2012;7:e33609.

    Not in our library10.1371/journal.pone.0033609 (opens in a new tab)

  232. 232.

    Chen J, et al. CDK 1‐mediated BCL 9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling. EMBO J. 2018;37:e99395.

    Not in our library10.15252/embj.201899395 (opens in a new tab)

  233. 233.

    Stauffer S, et al. CDK1-mediated mitotic phosphorylation of PBK is involved in cytokinesis and inhibits its oncogenic activity. Cell. Signal. 2017;39:74-83.

    Not in our library10.1016/j.cellsig.2017.08.001 (opens in a new tab)

  234. 234.

    Roskoski R. Src kinase regulation by phosphorylation and dephosphorylation. Biochem. Biophys. Res. Commun. 2005;331:1-14.

    Not in our library10.1016/j.bbrc.2005.03.012 (opens in a new tab)

  235. 235.

    Ulu A, Oh W, Zuo Y, Frost JA. Cdk1 phosphorylation negatively regulates the activity of Net1 towards RhoA during mitosis. Cell. Signal. 2021;80:109926.

    Not in our library10.1016/j.cellsig.2021.109926 (opens in a new tab)

  236. 236.

    Chen Y-J, et al. A conserved phosphorylation site within the forkhead domain of FoxM1B is required for its activation by cyclin-CDK1. J. Biol. Chem. 2009;284:30695-30707.

    Not in our library10.1074/jbc.m109.007997 (opens in a new tab)

  237. 237.

    Rajgopal A, et al. Mitotic control of RUNX2 phosphorylation by both CDK1/cyclin B kinase and PP1/PP2A phosphatase in osteoblastic cells. J. Cell. Biochem. 2007;100:1509-1517.

    Not in our library10.1002/jcb.21137 (opens in a new tab)

  238. 238.

    Dobrikov MI, Shveygert M, Brown MC, Gromeier M. Mitotic phosphorylation of eukaryotic initiation factor 4G1 (eIF4G1) at Ser1232 by Cdk1: cyclin B inhibits eIF4A helicase complex binding with RNA. Mol. Cell. Biol. 2014;34:439-451.

    Not in our library10.1128/mcb.01046-13 (opens in a new tab)

  239. 239.

    Fabbro M, et al. Cdk1/Erk2-and Plk1-dependent phosphorylation of a centrosome protein, Cep55, is required for its recruitment to midbody and cytokinesis. Dev. cell. 2005;9:477-488.

    Not in our library10.1016/j.devcel.2005.09.003 (opens in a new tab)

  240. 240.

    Zhang T, Prives C. Cyclin a-CDK phosphorylation regulates MDM2 protein interactions. J. Biol. Chem. 2001;276:29702-29710.

    Not in our library10.1074/jbc.m011326200 (opens in a new tab)

  241. 241.

    Liu R, et al. CDK1-mediated SIRT3 activation enhances mitochondrial function and tumor radioresistance. Mol. Cancer Therapeutics. 2015;14:2090-2102.

    Not in our library10.1158/1535-7163.mct-15-0017 (opens in a new tab)

  242. 242.

    Ferrero M, et al. Phosphorylation of AIB1 at mitosis is regulated by CDK1/CYCLIN B. PLoS ONE. 2011;6:e28602.

    Not in our library10.1371/journal.pone.0028602 (opens in a new tab)

  243. 243.

    Wei Y, et al. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat. Cell Biol. 2011;13:87-94.

    Not in our library10.1038/ncb2139 (opens in a new tab)

  244. 244.

    Matthess Y, Raab M, Knecht R, Becker S, Strebhardt K. Sequential Cdk1 and Plk1 phosphorylation of caspase-8 triggers apoptotic cell death during mitosis. Mol. Oncol. 2014;8:596-608.

    Not in our library10.1016/j.molonc.2013.12.013 (opens in a new tab)

  245. 245.

    Kaibori Y, Saito Y, Nakayama Y. EphA2 phosphorylation at Ser897 by the Cdk1/MEK/ERK/RSK pathway regulates M‐phase progression via maintenance of cortical rigidity. FASEB J. 2019;33:5334-5349.

    Not in our library10.1096/fj.201801519rr (opens in a new tab)

  246. 246.

    Garate M, Campos EI, Bush JA, Xiao H, Li G. Phosphorylation of the tumor suppressor p33ING1b at Ser‐126 influences its protein stability and proliferation of melanoma cells. FASEB J. 2007;21:3705-3716.

    Not in our library10.1096/fj.07-8069com (opens in a new tab)

  247. 247.

    Takata H, Madung M, Katoh K, Fukui K. Cdk1-dependent phosphorylation of KIF4A at S1186 triggers lateral chromosome compaction during early mitosis. PLoS ONE. 2018;13:e0209614.

    Not in our library10.1371/journal.pone.0209614 (opens in a new tab)

  248. 248.

    Zhang X, Wang Y. Cell cycle regulation of VCIP135 deubiquitinase activity and function in p97/p47-mediated Golgi reassembly. Mol. Biol. Cell. 2015;26:2242-2251.

    Not in our library10.1091/mbc.e15-01-0041 (opens in a new tab)

  249. 249.

    Wu JQ, et al. PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation. Nat. Cell Biol. 2009;11:644-651.

    Not in our library10.1038/ncb1871 (opens in a new tab)

  250. 250.

    Shi X, et al. Phosphorylation of STAT3 serine-727 by cyclin-dependent kinase 1 is critical for nocodazole-induced mitotic arrest. Biochemistry. 2006;45:5857-5867.

    Not in our library10.1021/bi052490j (opens in a new tab)

  251. 251.

    Harley ME, Allan LA, Sanderson HS, Clarke PR. Phosphorylation of Mcl‐1 by CDK1–cyclin B1 initiates its Cdc20‐dependent destruction during mitotic arrest. EMBO J. 2010;29:2407-2420.

    Not in our library10.1038/emboj.2010.112 (opens in a new tab)

  252. 252.

    Bertran MT, et al. Nek9 is a Plk1‐activated kinase that controls early centrosome separation through Nek6/7 and Eg5. EMBO J. 2011;30:2634-2647.

    Not in our library10.1038/emboj.2011.179 (opens in a new tab)

  253. 253.

    Tseng L-C, Chen R-H. Temporal control of nuclear envelope assembly by phosphorylation of lamin B receptor. Mol. Biol. Cell. 2011;22:3306-3317.

    Not in our library10.1091/mbc.e11-03-0199 (opens in a new tab)

  254. 254.

    Heald R, McKeon F. Mutations of phosphorylation sites in lamin A that prevent nuclear lamina disassembly in mitosis. Cell. 1990;61:579-589.

    Not in our library10.1016/0092-8674(90)90470-y (opens in a new tab)

  255. 255.

    Luo J, et al. The microtubule-associated protein EML3 regulates mitotic spindle assembly by recruiting the Augmin complex to spindle microtubules. J. Biol. Chem. 2019;294:5643-5656.

    Not in our library10.1074/jbc.ra118.007164 (opens in a new tab)

  256. 256.

    Maia AR, et al. Cdk1 and Plk1 mediate a CLASP2 phospho-switch that stabilizes kinetochore–microtubule attachments. J. Cell Biol. 2012;199:285-301.

    Not in our library10.1083/jcb.201203091 (opens in a new tab)

  257. 257.

    Kotak S, Busso C, Gönczy P. NuMA phosphorylation by CDK1 couples mitotic progression with cortical dynein function. EMBO J. 2013;32:2517-2529.

    Not in our library10.1038/emboj.2013.172 (opens in a new tab)

  258. 258.
    Cdk1-mediated DIAPH1 phosphorylation maintains metaphase cortical tension and inactivates the spindle assembly checkpoint at anaphase · 2019
    Not checked
  259. 259.

    Wu Z, Jiang Q, Clarke PR, Zhang C. Phosphorylation of Crm1 by CDK1–cyclin-B promotes Ran-dependent mitotic spindle assembly. J. Cell Sci. 2013;126:3417-3428.

    Not in our library10.1242/jcs.126854 (opens in a new tab)

  260. 260.

    Whalley HJ, et al. Cdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation. Nat. Commun. 2015;6:1-15.

    Not in our library10.1038/ncomms8437 (opens in a new tab)

  261. 261.

    Rapley J, et al. The NIMA-family kinase Nek6 phosphorylates the kinesin Eg5 at a novel site necessary for mitotic spindle formation. J. Cell Sci. 2008;121:3912-3921.

    Not in our library10.1242/jcs.035360 (opens in a new tab)

  262. 262.

    Zhang X, et al. Sequential phosphorylation of Nedd1 by Cdk1 and Plk1 is required for targeting of the γTuRC to the centrosome. J. Cell Sci. 2009;122:2240-2251.

    Not in our library10.1242/jcs.042747 (opens in a new tab)

  263. 263.

    Fourest-Lieuvin A, et al. Microtubule regulation in mitosis: tubulin phosphorylation by the cyclin-dependent kinase Cdk1. Mol. Biol. Cell. 2006;17:1041-1050.

    Not in our library10.1091/mbc.e05-07-0621 (opens in a new tab)

  264. 264.

    Schofield AV, Gamell C, Suryadinata R, Sarcevic B, Bernard O. Tubulin polymerization promoting protein 1 (Tppp1) phosphorylation by Rho-associated coiled-coil kinase (rock) and cyclin-dependent kinase 1 (Cdk1) inhibits microtubule dynamics to increase cell proliferation. J. Biol. Chem. 2013;288:7907-7917.

    Not in our library10.1074/jbc.m112.441048 (opens in a new tab)

  265. 265.

    Mori Y, Inoue Y, Taniyama Y, Tanaka S, Terada Y. Phosphorylation of the centrosomal protein, Cep169, by Cdk1 promotes its dissociation from centrosomes in mitosis. Biochem. Biophys. Res. Commun. 2015;468:642-646.

    Not in our library10.1016/j.bbrc.2015.11.004 (opens in a new tab)

  266. 266.

    Hong KU, et al. Cdk1-cyclin B1-mediated phosphorylation of tumor-associated microtubule-associated protein/cytoskeleton-associated protein 2 in mitosis. J. Biol. Chem. 2009;284:16501-16512.

    Not in our library10.1074/jbc.m900257200 (opens in a new tab)

  267. 267.

    Imami K, et al. Phosphorylation of the ribosomal protein RPL12/uL11 affects translation during mitosis. Mol. Cell. 2018;72:84-98.

    Not in our library10.1016/j.molcel.2018.08.019 (opens in a new tab)

  268. 268.

    Trinh AT, Kim SH, Chang H-Y, Mastrocola AS, Tibbetts RS. Cyclin-dependent kinase 1-dependent phosphorylation of cAMP response element-binding protein decreases chromatin occupancy. J. Biol. Chem. 2013;288:23765-23775.

    Not in our library10.1074/jbc.m113.464057 (opens in a new tab)

  269. 269.

    Yang H-C, et al. Pin1-mediated Sp1 phosphorylation by CDK1 increases Sp1 stability and decreases its DNA-binding activity during mitosis. Nucleic Acids Res. 2014;42:13573-13587.

    Not in our library10.1093/nar/gku1145 (opens in a new tab)

  270. 270.

    Sansregret L, et al. Hyperphosphorylation by cyclin B/CDK1 in mitosis resets CUX1 DNA binding clock at each cell cycle. J. Biol. Chem. 2010;285:32834-32843.

    Not in our library10.1074/jbc.m110.156406 (opens in a new tab)

  271. 271.

    Hackbarth JS, et al. Mitotic phosphorylation stimulates DNA relaxation activity of human topoisomerase I. J. Biol. Chem. 2008;283:16711-16722.

    Not in our library10.1074/jbc.m802246200 (opens in a new tab)

  272. 272.

    Murphy LA, Sarge KD. Phosphorylation of CAP-G is required for its chromosomal DNA localization during mitosis. Biochem. Biophys. Res. Commun. 2008;377:1007-1011.

    Not in our library10.1016/j.bbrc.2008.10.114 (opens in a new tab)

  273. 273.

    Hou Y, Allan LA, Clarke PR. Phosphorylation of XIAP by CDK1–cyclin-B1 controls mitotic cell death. J. Cell Sci. 2017;130:502-511.

    Not in our library10.1242/jcs.192310 (opens in a new tab)

  274. 274.

    Su Y-F, Yang T, Huang H, Liu LF, Hwang J. Phosphorylation of Ubc9 by Cdk1 enhances SUMOylation activity. PLoS ONE. 2012;7:e34250.

    Not in our library10.1371/journal.pone.0034250 (opens in a new tab)

  275. 275.

    Sun C, Zheng J, Cheng S, Feng D, He J. EBP50 phosphorylation by Cdc2/Cyclin B kinase affects actin cytoskeleton reorganization and regulates functions of human breast cancer cell line MDA-MB-231. Mol. Cells. 2013;36:47-54.

    Not in our library10.1007/s10059-013-0014-0 (opens in a new tab)

  276. 276.

    Cukier IH, Li Y, Lee JM. Cyclin B1/Cdk1 binds and phosphorylates Filamin A and regulates its ability to cross-link actin. FEBS Lett. 2007;581:1661-1672.

    Not in our library10.1016/j.febslet.2007.03.041 (opens in a new tab)

  277. 277.
    Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis · 2020
    No notice
  278. 278.

    Marceaux C, Petit D, Bertoglio J, David MD. Phosphorylation of ARHGAP19 by CDK1 and ROCK regulates its subcellular localization and function during mitosis. J. Cell Sci. 2018;131:jcs208397.

    Not in our library10.1242/jcs.208397 (opens in a new tab)

  279. 279.

    Helms MC, et al. Mitotic-dependent phosphorylation of leukemia-associated RhoGEF (LARG) by Cdk1. Cell. Signal. 2016;28:43-52.

    Not in our library10.1016/j.cellsig.2015.10.004 (opens in a new tab)

  280. 280.

    Nakamura A, Naito M, Arai H, Fujita N. Mitotic phosphorylation of Aki1 at Ser208 by cyclin B1–Cdk1 complex. Biochem. Biophys. Res. Commun. 2010;393:872-876.

    Not in our library10.1016/j.bbrc.2010.02.103 (opens in a new tab)

  281. 281.

    Diao A, Frost L, Morohashi Y, Lowe M. Coordination of golgin tethering and SNARE assembly: GM130 binds syntaxin 5 in a p115-regulated manner. J. Biol. Chem. 2008;283:6957-6967.

    Not in our library10.1074/jbc.m708401200 (opens in a new tab)

  282. 282.

    Lin DI, Aggarwal P, Diehl JA. Phosphorylation of MCM3 on Ser-112 regulates its incorporation into the MCM2–7 complex. Proc. Natl Acad. Sci. 2008;105:8079-8084.

    Not in our library10.1073/pnas.0800077105 (opens in a new tab)

  283. 283.

    Dreier MR, Bekier ME, Taylor WR. Regulation of sororin by Cdk1-mediated phosphorylation. J. Cell Sci. 2011;124:2976-2987.

    Not in our library10.1242/jcs.085431 (opens in a new tab)

  284. 284.

    Borton MT, Rashid MS, Dreier MR, Taylor WR. Multiple levels of regulation of Sororin by Cdk1 and Aurora B. J. Cell. Biochem. 2016;117:351-360.

    Not in our library10.1002/jcb.25277 (opens in a new tab)

  285. 285.

    Shah OJ, Ghosh S, Hunter T. Mitotic regulation of ribosomal S6 kinase 1 involves Ser/Thr, Pro phosphorylation of consensus and non-consensus sites by Cdc2. J. Biol. Chem. 2003;278:16433-16442.

    Not in our library10.1074/jbc.m300435200 (opens in a new tab)

  286. 286.

    Bassermann F, et al. Multisite Phosphorylation of Nuclear Interaction Partner of ALK (NIPA) at G2/M Involves Cyclin B1/Cdk1*♦. J. Biol. Chem. 2007;282:15965-15972.

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    Raghavan P, et al. AZD5438, an inhibitor of Cdk1, 2, and 9, enhances the radiosensitivity of non-small cell lung carcinoma cells. Int. J. Radiat. Oncol.* Biol.* Phys. 2012;84:e507-e514.

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    Yu F, et al. Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene. 2011;30:2161-2172.

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