The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.

References 82

1. 1.

   Adams CM. Role of the transcription factor ATF4 in the anabolic actions of insulin and the anti-anabolic actions of glucocorticoids. Journal of Biological Chemistry. 2007;282:16744-16753.

   Not in our library10.1074/jbc.m610510200

2. 2.

   Arts GJ, Kuersten S, Romby P, Ehresmann B, Mattaj IW. The role of exportin-t in selective nuclear export of mature tRNAs. The EMBO Journal. 1998;17:7430-7441.

   Not in our library10.1093/emboj/17.24.7430

3. 3.

   Bannai S, Kitamura E. Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture. Journal of Biological Chemistry. 1980;255:2372-2376.

   Not in our library10.1016/s0021-9258(19)85901-x

4. 4.

   Ben-Sahra I, Hoxhaj G, Ricoult SJH, Asara JM, Manning BD. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science. 2016;351:728-733.

   Not in our library10.1126/science.aad0489

5. 5.

   Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell. 2003;4:147-158.

   Not in our library10.1016/s1535-6108(03)00187-9

6. 6.

   Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes & Development. 2004;18:2893-2904.

   Not in our library10.1101/gad.1256804

7. 7.

   Clemens MJ. Protein kinases that phosphorylate eIF2 and eIF2B, and their role in eukaryotic cell translational control. Translational Control. 1996;30:139-172.

   Not in our library10.1101/0.139-172

8. 8.

   Cohen DM, Won KJ, Nguyen N, Lazar MA, Chen CS, Steger DJ. ATF4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis. eLife. 2015;4:e06821.

   Not in our library10.7554/elife.06821

9. 9.

   Condon KJ, Orozco JM, Adelmann CH, Spinelli JB, van der Helm PW, Roberts JM, Kunchok T, Sabatini DM. Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction. PNAS. 2021;118:e2022120118.

   Not in our library10.1073/pnas.2022120118

10. 10.

    Conrad M, Sato H. The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (-): cystine supplier and beyond. Amino Acids. 2012;42:231-246.

    Not in our library10.1007/s00726-011-0867-5

11. 11.

    Csibi A, Lee G, Yoon SO, Tong H, Ilter D, Elia I, Fendt SM, Roberts TM, Blenis J. The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation. Current Biology. 2014;24:2274-2280.

    Not in our library10.1016/j.cub.2014.08.007

12. 12.
    CRISP-ID: decoding CRISPR mediated indels by Sanger sequencing · 2016

    No notice
13. 13.

    Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Molecular Cell. 2010;39:171-183.

    Not in our library10.1016/j.molcel.2010.06.022

14. 14.

    Ebert SM, Bullard SA, Basisty N, Marcotte GR, Skopec ZP, Dierdorff JM, Al-Zougbi A, Tomcheck KC, DeLau AD, Rathmacher JA, Bodine SC, Schilling B, Adams CM. Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ. Journal of Biological Chemistry. 2020;295:2787-2803.

    Not in our library10.1074/jbc.ra119.012095

15. 15.
    CiiiDER: A tool for predicting and analysing transcription factor binding sites · 2019

    No notice
16. 16.

    Griffith OW, Meister A. Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). Journal of Biological Chemistry. 1979;254:7558-7560.

    Not in our library10.1016/s0021-9258(18)35980-5

17. 17.

    Gu Y, Albuquerque CP, Braas D, Zhang W, Villa GR, Bi J, Ikegami S, Masui K, Gini B, Yang H, Gahman TC, Shiau AK, Cloughesy TF, Christofk HR, Zhou H, Guan KL, Mischel PS. mTORC2 regulates amino acid metabolism in Cancer by phosphorylation of the Cystine-Glutamate antiporter xCT. Molecular Cell. 2017;67:128-138.

    Not in our library10.1016/j.molcel.2017.05.030

18. 18.

    Habib E, Linher-Melville K, Lin HX, Singh G. Expression of xCT and activity of system xc(-) are regulated by NRF2 in human breast Cancer cells in response to oxidative stress. Redox Biology. 2015;5:33-42.

    Not in our library10.1016/j.redox.2015.03.003

19. 19.

    Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, Kilberg MS, Sartor MA, Kaufman RJ. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nature Cell Biology. 2013;15:481-490.

    Not in our library10.1038/ncb2738

20. 20.

    Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Molecular Cell. 2000;6:1099-1108.

    Not in our library10.1016/s1097-2765(00)00108-8

21. 21.

    Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Molecular Cell. 2003;11:619-633.

    Not in our library10.1016/s1097-2765(03)00105-9

22. 22.

    He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J. Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. implication for heme oxygenase-1 gene regulation. The Journal of Biological Chemistry. 2001;276:20858-20865.

    Not in our library10.1074/jbc.m101198200

23. 23.

    Heigwer F, Kerr G, Boutros M. E-CRISP: fast CRISPR target site identification. Nature Methods. 2014;11:122-123.

    Not in our library10.1038/nmeth.2812

24. 24.

    Hodges LC, Houston KD, Hunter DS, Fuchs-Young R, Zhang Z, Wineker RC, Walker CL. Transdominant suppression of estrogen receptor signaling by progesterone receptor ligands in uterine leiomyoma cells. Molecular and Cellular Endocrinology. 2002;196:11-20.

    Not in our library10.1016/s0303-7207(02)00230-7

25. 25.

    Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123:569-580.

    Not in our library10.1016/j.cell.2005.10.024

26. 26.

    Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. Journal of Clinical Investigation. 2002;109:1125-1131.

    Not in our library10.1172/jci0215593

27. 27.

    Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Molecular and Cellular Biology. 2002;22:7004-7014.

    Not in our library10.1128/mcb.22.20.7004-7014.2002

28. 28.

    Huggins CJ, Mayekar MK, Martin N, Saylor KL, Gonit M, Jailwala P, Kasoji M, Haines DC, Quiñones OA, Johnson PF. C/EBPγ is a critical regulator of cellular stress response networks through heterodimerization with ATF4. Molecular and Cellular Biology. 2015;36:693-713.

    Not in our library10.1128/mcb.00911-15

29. 29.

    Jefferies HB, Reinhard C, Kozma SC, Thomas G. Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. PNAS. 1994;91:4441-4445.

    Not in our library10.1073/pnas.91.10.4441

30. 30.

    Kilberg MS, Shan J, Su N. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends in Endocrinology & Metabolism. 2009;20:436-443.

    Not in our library10.1016/j.tem.2009.05.008

31. 31.

    Kong H, Chandel NS. Regulation of redox balance in Cancer and T cells. Journal of Biological Chemistry. 2018;293:7499-7507.

    Not in our library10.1074/jbc.tm117.000257

32. 32.

    Kutay U, Lipowsky G, Izaurralde E, Bischoff FR, Schwarzmaier P, Hartmann E, Görlich D. Identification of a tRNA-specific nuclear export receptor. Molecular Cell. 1998;1:359-369.

    Not in our library10.1016/s1097-2765(00)80036-2

33. 33.

    Lam HC, Baglini CV, Lope AL, Parkhitko AA, Liu HJ, Alesi N, Malinowska IA, Ebrahimi-Fakhari D, Saffari A, Yu JJ, Pereira A, Khabibullin D, Ogorek B, Nijmeh J, Kavanagh T, Handen A, Chan SY, Asara JM, Oldham WM, Diaz-Meco MT, Moscat J, Sahin M, Priolo C, Henske EP. p62/SQSTM1 cooperates with hyperactive mTORC1 to regulate glutathione production, maintain mitochondrial integrity, and promote tumorigenesis. Cancer Research. 2017;77:3255-3267.

    Not in our library10.1158/0008-5472.can-16-2458

34. 34.

    Lange PS, Chavez JC, Pinto JT, Coppola G, Sun CW, Townes TM, Geschwind DH, Ratan RR. ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. Journal of Experimental Medicine. 2008;205:1227-1242.

    Not in our library10.1084/jem.20071460

35. 35.

    Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Molecular and Cellular Biology. 2001;21:3995-4004.

    Not in our library10.1128/mcb.21.12.3995-4004.2001

36. 36.

    Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, Ocorr K, Ellisman MH, Bodmer R, Bier E, Karin M. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science. 2010;327:1223-1228.

    Not in our library10.1126/science.1182228

37. 37.

    Li C, Chen H, Lan Z, He S, Chen R, Wang F, Liu Z, Li K, Cheng L, Liu Y, Sun K, Wan X, Chen X, Peng H, Li L, Zhang Y, Jing Y, Huang M, Wang Y, Wang Y, Jiang J, Zha X, Chen L, Zhang H. mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis. Cell Death & Differentiation. 2019;26:2015-2028.

    Not in our library10.1038/s41418-019-0274-0

38. 38.

    Liao Y, Smyth GK, Shi W. The R package rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads. Nucleic Acids Research. 2019;47:e47.

    Not in our library10.1093/nar/gkz114

39. 39.

    Lien EC, Ghisolfi L, Geck RC, Asara JM, Toker A. Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT. Science Signaling. 2017;10:eaao6604.

    Not in our library10.1126/scisignal.aao6604

40. 40.

    Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nature Reviews. Molecular Cell Biology. 2009;10:307-318.

    Not in our library10.1038/nrm2672

41. 41.

    Mei S, Qin Q, Wu Q, Sun H, Zheng R, Zang C, Zhu M, Wu J, Shi X, Taing L, Liu T, Brown M, Meyer CA, Liu XS. Cistrome data browser: a data portal for ChIP-Seq and chromatin accessibility data in human and mouse. Nucleic Acids Research. 2017;45:D658-D662.

    Not in our library10.1093/nar/gkw983

42. 42.

    Meister A. Selective modification of glutathione metabolism. Science. 1983;220:472-477.

    Not in our library10.1126/science.6836290

43. 43.

    Nakazawa MS, Keith B, Simon MC. Oxygen availability and metabolic adaptations. Nature Reviews Cancer. 2016;16:663-673.

    Not in our library10.1038/nrc.2016.84

44. 44.

    Newman JR, Keating AE. Comprehensive identification of human bZIP interactions with coiled-coil arrays. Science. 2003;300:2097-2101.

    Not in our library10.1126/science.1084648

45. 45.

    Owen JL, Zhang Y, Bae SH, Farooqi MS, Liang G, Hammer RE, Goldstein JL, Brown MS. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. PNAS. 2012;109:16184-16189.

    Not in our library10.1073/pnas.1213343109

46. 46.

    Ozcan U, Ozcan L, Yilmaz E, Düvel K, Sahin M, Manning BD, Hotamisligil GS. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Molecular Cell. 2008;29:541-551.

    Not in our library10.1016/j.molcel.2007.12.023

47. 47.

    Park Y, Reyna-Neyra A, Philippe L, Thoreen CC. mTORC1 balances cellular amino acid supply with demand for protein synthesis through Post-transcriptional control of ATF4. Cell Reports. 2017;19:1083-1090.

    Not in our library10.1016/j.celrep.2017.04.042

48. 48.

    Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell. 2011;146:408-420.

    Not in our library10.1016/j.cell.2011.06.034

49. 49.

    Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metabolism. 2008;8:224-236.

    Not in our library10.1016/j.cmet.2008.07.007

50. 50.

    Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nature Protocols. 2013;8:2281-2308.

    Not in our library10.1038/nprot.2013.143

51. 51.

    Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD, Sonenberg N, Hershey JW. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. The EMBO Journal. 2004;23:1761-1769.

    Not in our library10.1038/sj.emboj.7600193

52. 52.

    Reiling JH, Hafen E. The hypoxia-induced paralogs Scylla and charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes & Development. 2004;18:2879-2892.

    Not in our library10.1101/gad.322704

53. 53.
    limma powers differential expression analyses for RNA-sequencing and microarray studies · 2015

    No notice
54. 54.

    Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139-140.

    Not in our library10.1093/bioinformatics/btp616

55. 55.

    Sabò A, Kress TR, Pelizzola M, de Pretis S, Gorski MM, Tesi A, Morelli MJ, Bora P, Doni M, Verrecchia A, Tonelli C, Fagà G, Bianchi V, Ronchi A, Low D, Müller H, Guccione E, Campaner S, Amati B. Selective transcriptional regulation by myc in cellular growth control and lymphomagenesis. Nature. 2014;511:488-492.

    Not in our library10.1038/nature13537

56. 56.

    Sasaki H, Sato H, Kuriyama-Matsumura K, Sato K, Maebara K, Wang H, Tamba M, Itoh K, Yamamoto M, Bannai S. Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. Journal of Biological Chemistry. 2002;277:44765-44771.

    Not in our library10.1074/jbc.m208704200

57. 57.

    Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S, Kaufman RJ. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Molecular Cell. 2001;7:1165-1176.

    Not in our library10.1016/s1097-2765(01)00265-9

58. 58.

    Schuhmacher M, Eick D. Dose-dependent regulation of target gene expression and cell proliferation by c-Myc levels. Transcription. 2013;4:192-197.

    Not in our library10.4161/trns.25907

59. 59.

    Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer. Cancer Discovery. 2015;5:1024-1039.

    Not in our library10.1158/2159-8290.cd-15-0507

60. 60.

    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. PNAS. 2005;102:15545-15550.

    Not in our library10.1073/pnas.0506580102

61. 61.

    Tang Y, El-Chemaly S, Taveira-Dasilva A, Goldberg HJ, Bagwe S, Rosas IO, Moss J, Priolo C, Henske EP. Alterations in polyamine metabolism in patients with lymphangioleiomyomatosis and tuberous sclerosis complex 2-Deficient cells. Chest. 2019;156:1137-1148.

    Not in our library10.1016/j.chest.2019.05.038

62. 62.

    Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, Czernin J, Sawyers CL. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney Cancer. Nature Medicine. 2006;12:122-127.

    Not in our library10.1038/nm1337

63. 63.

    Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature. 2012;485:109-113.

    Not in our library10.1038/nature11083

64. 64.

    Torrence ME, Manning BD. Nutrient sensing in cancer. Annual Review of Cancer Biology. 2018;2:251-269.

    Not in our library10.1146/annurev-cancerbio-030617-050329

65. 65.

    Valvezan AJ, Turner M, Belaid A, Lam HC, Miller SK, McNamara MC, Baglini C, Housden BE, Perrimon N, Kwiatkowski DJ, Asara JM, Henske EP, Manning BD. mTORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability. Cancer Cell. 2017;32:624-638.

    Not in our library10.1016/j.ccell.2017.09.013

66. 66.

    Valvezan AJ, Manning BD. Molecular logic of mTORC1 signalling as a metabolic rheostat. Nature Metabolism. 2019;1:321-333.

    Not in our library10.1038/s42255-019-0038-7

67. 67.

    Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. PNAS. 2004;101:11269-11274.

    Not in our library10.1073/pnas.0400541101

68. 68.

    Wall M, Poortinga G, Hannan KM, Pearson RB, Hannan RD, McArthur GA. Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation. Blood. 2008;112:2305-2317.

    Not in our library10.1182/blood-2007-09-111856

69. 69.

    Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081-1086.

    Not in our library10.1126/science.1209038

70. 70.

    Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, Rycak L, Dumay-Odelot H, Karim S, Bartkuhn M, Roels F, Wüstefeld T, Fischer M, Teichmann M, Zender L, Wei CL, Sansom O, Wolf E, Eilers M. Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature. 2014;511:483-487.

    Not in our library10.1038/nature13473

71. 71.

    Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR, Sabatini DM. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016;351:43-48.

    Not in our library10.1126/science.aab2674

72. 72.

    Wortel IMN, van der Meer LT, Kilberg MS, van Leeuwen FN. Surviving stress: modulation of ATF4-Mediated stress responses in normal and malignant cells. Trends in Endocrinology & Metabolism. 2017;28:794-806.

    Not in our library10.1016/j.tem.2017.07.003

73. 73.

    Wu H, Wei L, Fan F, Ji S, Zhang S, Geng J, Hong L, Fan X, Chen Q, Tian J, Jiang M, Sun X, Jin C, Yin ZY, Liu Q, Zhang J, Qin F, Lin KH, Yu JS, Deng X, Wang HR, Zhao B, Johnson RL, Chen L, Zhou D. Integration of hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. Nature Communications. 2015;6:6239.

    Not in our library10.1038/ncomms7239

74. 74.

    Xiao Y, Hill MC, Li L, Deshmukh V, Martin TJ, Wang J, Martin JF. Hippo pathway deletion in adult resting cardiac fibroblasts initiates a cell state transition with spontaneous and self-sustaining fibrosis. Genes & Development. 2019;33:1491-1505.

    Not in our library10.1101/gad.329763.119

75. 75.

    Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring Cancer cells. Chemistry & Biology. 2008;15:234-245.

    Not in our library10.1016/j.chembiol.2008.02.010

76. 76.

    Ye P, Mimura J, Okada T, Sato H, Liu T, Maruyama A, Ohyama C, Itoh K. Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition. Molecular and Cellular Biology. 2014;34:3421-3434.

    Not in our library10.1128/mcb.00221-14

77. 77.

    Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS: A Journal of Integrative Biology. 2012;16:284-287.

    Not in our library10.1089/omi.2011.0118

78. 78.

    Zarei M, Du H, Nassar AH, Yan RE, Giannikou K, Johnson SH, Lam HC, Henske EP, Wang Y, Zhang T, Asara J, Kwiatkowski DJ. Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion. Journal of Experimental Medicine. 2019;216:2635-2652.

    Not in our library10.1084/jem.20190251

79. 79.

    Zhang Y, Nicholatos J, Dreier JR, Ricoult SJ, Widenmaier SB, Hotamisligil GS, Kwiatkowski DJ, Manning BD. Coordinated regulation of protein synthesis and degradation by mTORC1. Nature. 2014;513:440-443.

    Not in our library10.1038/nature13492

80. 80.

    Zheng R, Wan C, Mei S, Qin Q, Wu Q, Sun H, Chen CH, Brown M, Zhang X, Meyer CA, Liu XS. Cistrome data browser: expanded datasets and new tools for gene regulatory analysis. Nucleic Acids Research. 2019;47:D729-D735.

    Not in our library10.1093/nar/gky1094

81. 81.

    Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate Cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Research. 2000;60:1541-1545.

    Not in our library

82. 82.

    Zirin J, Ni X, Sack LM, Yang-Zhou D, Hu Y, Brathwaite R, Bulyk ML, Elledge SJ, Perrimon N. Interspecies analysis of MYC targets identifies tRNA synthetases as mediators of growth and survival in MYC-overexpressing cells. PNAS. 2019;116:14614-14619.

    Not in our library10.1073/pnas.1821863116

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