Saga of Mcl-1: regulation from transcription to degradation

Abstract

The members of the Bcl-2 family are the central regulators of various cell death modalities. Some of these proteins contribute to apoptosis, while others counteract this type of programmed cell death, thus balancing cell demise and survival. A disruption of this balance leads to the development of various diseases, including cancer. Therefore, understanding the mechanisms that underlie the regulation of proteins of the Bcl-2 family is of great importance for biomedical research. Among the members of the Bcl-2 family, antiapoptotic protein Mcl-1 is characterized by a short half-life, which renders this protein highly sensitive to changes in its synthesis or degradation. Hence, the regulation of Mcl-1 is of particular scientific interest, and the study of Mcl-1 modulators could aid in the understanding of the mechanisms of disease development and the ways of their treatment. Here, we summarize the present knowledge regarding the regulation of Mcl-1, from transcription to degradation, focusing on aspects that have not yet been described in detail.

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Fig. 1: Phosphorylation, ubiquitination, and deubiquitination of Mcl-1.
Fig. 2: Degradation of Mcl-1 upon treatment with antimitotic drugs.

References

  1. 1.

    Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl Acad Sci USA. 1993;90:3516–20.

    CAS  PubMed  Google Scholar 

  2. 2.

    Lin EY, Orlofsky A, Berger MS, Prystowsky MB. Characterization of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. J Immunol. 1993;151:1979–88.

    CAS  PubMed  Google Scholar 

  3. 3.

    Boise LH, González-García M, Postema CE, Ding L, Lindsten T, Turka LA, et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993;74:597–608.

    CAS  PubMed  Google Scholar 

  4. 4.

    Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74:609–19.

    CAS  PubMed  Google Scholar 

  5. 5.

    Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988;335:440–2.

    CAS  PubMed  Google Scholar 

  6. 6.

    Merino D, Kelly GL, Lessene G, Wei AH, Roberts AW, Strasser A. BH3-mimetic drugs: blazing the trail for new cancer medicines. Cancer Cell. 2018;34:879–91.

    CAS  PubMed  Google Scholar 

  7. 7.

    Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol. 2019;20:175–93.

    CAS  PubMed  Google Scholar 

  8. 8.

    Hird AW, Tron AE. Recent advances in the development of Mcl-1 inhibitors for cancer therapy. Pharm Ther. 2019;198:59–67.

    CAS  Google Scholar 

  9. 9.

    Senichkin VV, Streletskaia AY, Zhivotovsky B, Kopeina GS. Molecular comprehension of Mcl-1: from gene structure to cancer therapy. Trends Cell Biol. 2019. https://doi.org/10.1016/j.tcb.2019.03.004.

    CAS  PubMed  Google Scholar 

  10. 10.

    Craig RW. MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis. Leukemia. 2002;16:444–54.

    CAS  PubMed  Google Scholar 

  11. 11.

    Thomas LW, Lam C, Edwards SW. Mcl-1; the molecular regulation of protein function. FEBS Lett. 2010;584:2981–9.

    CAS  PubMed  Google Scholar 

  12. 12.

    Gores GJ, Kaufmann SH. Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors. Genes Dev. 2012;26:305–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Mojsa B, Lassot I, Desagher S. Mcl-1 ubiquitination: unique regulation of an essential survival protein. Cells. 2014;3:418–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Opferman JT. Attacking cancer’s Achilles heel: antagonism of anti-apoptotic BCL-2 family members. FEBS J. 2016;283:2661–75.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2013;15:49–63.

    Google Scholar 

  16. 16.

    Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997;90:405–13.

    CAS  PubMed  Google Scholar 

  17. 17.

    Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10:375–88.

    CAS  PubMed  Google Scholar 

  18. 18.

    Rogers S, Wells R, Rechsteiner M. Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis. Science. 1986;234:364–8.

    CAS  Google Scholar 

  19. 19.

    Liu H, Peng H-W, Cheng Y-S, Yuan HS, Yang-Yen H-F. Stabilization and enhancement of the antiapoptotic activity of mcl-1 by TCTP. Mol Cell Biol. 2005;25:3117–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Bingle CD, Craig RW, Swales BM, Singleton V, Zhou P, Whyte MKB. Exon skipping in Mcl-1 results in a Bcl-2 homology domain 3 only gene product that promotes cell death. J Biol Chem. 2000;275:22136–46.

    CAS  PubMed  Google Scholar 

  21. 21.

    Kim J-H, Sim S-H, Ha H-J, Ko J-J, Lee K, Bae J. MCL-1ES, a novel variant of MCL-1, associates with MCL-1L and induces mitochondrial cell death. FEBS Lett. 2009;583:2758–64.

    CAS  PubMed  Google Scholar 

  22. 22.

    Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC, Korsmeyer SJ. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature. 2003;426:671–6.

    CAS  PubMed  Google Scholar 

  23. 23.

    Arbour N, Vanderluit JL, Le Grand JN, Jahani-Asl A, Ruzhynsky VA, Cheung ECC, et al. Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage. J Neurosci. 2008;28:6068–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Wang X, Bathina M, Lynch J, Koss B, Calabrese C, Frase S, et al. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes Dev. 2013;27:1351–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Xiang Z, Luo H, Payton JE, Cain J, Ley TJ, Opferman JT, et al. Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia. J Clin Invest. 2010;120:2109–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Sieghart W, Losert D, Strommer S, Cejka D, Schmid K, Rasoul-Rockenschaub S, et al. Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy. J Hepatol. 2006;44:151–7.

    CAS  PubMed  Google Scholar 

  27. 27.

    Wesarg E, Hoffarth S, Wiewrodt R, Kröll M, Biesterfeld S, Huber C, et al. Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer. Int J Cancer. 2007;121:2387–94.

    CAS  PubMed  Google Scholar 

  28. 28.

    Campbell KJ, Dhayade S, Ferrari N, Sims AH, Johnson E, Mason SM, et al. MCL-1 is a prognostic indicator and drug target in breast cancer. Cell Death Dis. 2018;9:19.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357:eaan2507.

    PubMed  Google Scholar 

  30. 30.

    Niu X, Zhao J, Ma J, Xie C, Edwards H, Wang G, et al. Binding of released Bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells. Clin Cancer Res. 2016;22:4440–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Wu X, Luo Q, Zhao P, Chang W, Wang Y, Shu T, et al. MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer. Proc Natl Acad Sci USA. 2019;116:2961–6.

    CAS  PubMed  Google Scholar 

  32. 32.

    Wu X, Luo Q, Zhao P, Chang W, Wang Y, Shu T, et al. JOSD1 inhibits mitochondrial apoptotic signalling to drive acquired chemoresistance in gynaecological cancer by stabilizing MCL1. Cell Death Differ. 2019. https://doi.org/10.1038/s41418-019-0339-0.

    Google Scholar 

  33. 33.

    Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Kaufmann SH, Karp JE, Svingen PA, Krajewski S, Burke PJ, Gore SD, et al. Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood. 1998;91:991–1000.

    CAS  PubMed  Google Scholar 

  35. 35.

    Jourdan M, De Vos J, Mechti N, Klein B. Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1. Cell Death Differ. 2000;7:1244–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Schulze-Bergkamen H, Brenner D, Krueger A, Suess D, Fas SC, Frey CR, et al. Hepatocyte growth factor induces Mcl-1 in primary human hepatocytes and inhibits CD95-mediated apoptosis via Akt. Hepatology. 2004;39:645–54.

    CAS  PubMed  Google Scholar 

  37. 37.

    Leu C-M, Chang C, Hu C. Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway. Oncogene. 2000;19:1665–75.

    CAS  PubMed  Google Scholar 

  38. 38.

    Booy EP, Henson ES, Gibson SB. Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer. Oncogene. 2011;30:2367–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Yang T, Buchan HL, Townsend KJ, Craig RW. MCL-1, a member of the BCL-2 family, is induced rapidly in response to signals for cell differentiation or death, but not to signals for cell proliferation. J Cell Physiol. 1996;166:523–36.

    CAS  PubMed  Google Scholar 

  40. 40.

    Jiang CC, Lucas K, Avery-Kiejda KA, Wade M, deBock CE, Thorne RF, et al. Up-regulation of Mcl-1 Is critical for survival of human melanoma cells upon endoplasmic reticulum stress. Cancer Res. 2008;68:6708–17.

    CAS  PubMed  Google Scholar 

  41. 41.

    Piret J-P, Minet E, Cosse J-P, Ninane N, Debacq C, Raes M, et al. Hypoxia-inducible factor-1-dependent overexpression of myeloid cell factor-1 protects hypoxic cells against tert-butyl hydroperoxide-induced apoptosis. J Biol Chem. 2005;280:9336–44.

    CAS  PubMed  Google Scholar 

  42. 42.

    Sheng Z, Li L, Zhu LJ, Smith TW, Demers A, Ross AH, et al. A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications. Nat Med. 2010;16:671–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Kiprianova I, Remy J, Milosch N, Mohrenz IV, Seifert V, Aigner A, et al. Sorafenib sensitizes glioma cells to the BH3 mimetic ABT-737 by targeting MCL1 in a STAT3-dependent manner. Neoplasia. 2015;17:564–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Cui J, Placzek WJ. Post-transcriptional regulation of anti-apoptotic BCL2 family members. Int J Mol Sci. 2018; 19. https://doi.org/10.3390/IJMS19010308.

  45. 45.

    Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Fritsch RM, Schneider G, Saur D, Scheibel M, Schmid RM. Translational repression of MCL-1 couples stress-induced eIF2α phosphorylation to mitochondrial apoptosis initiation. J Biol Chem. 2007;282:22551–62.

    CAS  PubMed  Google Scholar 

  47. 47.

    De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene. 2004;23:3189–99.

    PubMed  Google Scholar 

  48. 48.

    Mills JR, Hippo Y, Robert F, Chen SMH, Malina A, Lin C-J, et al. mTORC1 promotes survival through translational control of Mcl-1. Proc Natl Acad Sci. 2008;105:10853–8.

    CAS  PubMed  Google Scholar 

  49. 49.

    Pradelli LA, Bénéteau M, Chauvin C, Jacquin MA, Marchetti S, Muñoz-Pinedo C, et al. Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation. Oncogene. 2010;29:1641–52.

    CAS  PubMed  Google Scholar 

  50. 50.

    Tailler M, Lindqvist LM, Gibson L, Adams JM. By reducing global mRNA translation in several ways, 2-deoxyglucose lowers MCL-1 protein and sensitizes hemopoietic tumor cells to BH3 mimetic ABT737. Cell Death Differ. 2018. https://doi.org/10.1038/s41418-018-0244-y.

    Google Scholar 

  51. 51.

    Kim SM, Yun MR, Hong YK, Solca F, Kim JH, Kim HJ, et al. Glycolysis inhibition sensitizes non-small cell lung cancer with T790M mutation to irreversible EGFR inhibitors via translational suppression of Mcl-1 by AMPK activation. Mol Cancer Ther. 2013;12:2145–56.

    CAS  PubMed  Google Scholar 

  52. 52.

    Pawson T, Scott JD. Protein phosphorylation in signaling—50 years and counting. Trends Biochem Sci. 2005;30:286–90.

    CAS  PubMed  Google Scholar 

  53. 53.

    Zamaraev AV, Kopeina GS, Prokhorova EA, Zhivotovsky B, Lavrik IN. Post-translational modification of caspases: the other side of apoptosis regulation. Trends Cell Biol. 2017;27:322–39.

    CAS  PubMed  Google Scholar 

  54. 54.

    Domina AM, Vrana JA, Gregory MA, Hann SR, Craig RW. MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells and at additional sites with cytotoxic okadaic acid or taxol. Oncogene. 2004;23:5301–15.

    CAS  PubMed  Google Scholar 

  55. 55.

    Ding Q, Huo L, Yang J-Y, Xia W, Wei Y, Liao Y, et al. Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer. Cancer Res. 2008;68:6109–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, et al. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature. 2011;471:104–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006;21:749–60.

    CAS  PubMed  Google Scholar 

  58. 58.

    Ding Q, He X, Hsu J-M, Xia W, Chen C-T, Li L-Y, et al. Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol. 2007;27:4006–17.

    CAS  PubMed  Google Scholar 

  59. 59.

    Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011;471:110–4.

    CAS  PubMed  Google Scholar 

  60. 60.

    Tong J, Zheng X, Tan X, Fletcher R, Nikolovska-Coleska Z, Yu J, et al. Mcl-1 phosphorylation without degradation mediates sensitivity to HDAC inhibitors by liberating BH3-only proteins. Cancer Res. 2018;78:4704–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    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;29:2407–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Chu R, Alford SE, Hart K, Kothari A, Mackintosh SG, Kovak MR, et al. Mitotic arrest-induced phosphorylation of Mcl-1 revisited using two-dimensional gel electrophoresis and phosphoproteomics: nine phosphorylation sites identified. Oncotarget. 2016;7:78958–70.

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Kobayashi S, Lee S-H, Meng XW, Mott JL, Bronk SF, Werneburg NW, et al. Serine 64 phosphorylation enhances the antiapoptotic function of Mcl-1. J Biol Chem. 2007;282:18407–17.

    CAS  PubMed  Google Scholar 

  64. 64.

    Nakajima W, Sharma K, Lee JY, Maxim NT, Hicks MA, Vu T-T, et al. DNA damaging agent-induced apoptosis is regulated by MCL-1 phosphorylation and degradation mediated by the Noxa/MCL-1/CDK2 complex. Oncotarget. 2016;7:36353–65.

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Inoshita S, Takeda K, Hatai T, Terada Y, Sano M, Hata J, et al. Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress. J Biol Chem. 2002;277:43730–4.

    CAS  PubMed  Google Scholar 

  66. 66.

    Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005;19:1294–305.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Chau V, Tobias JW, Bachmair A, Marriott D, Ecker DJ, Gonda DK, et al. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science. 1989;243:1576–83.

    CAS  PubMed  Google Scholar 

  68. 68.

    Stewart DP, Koss B, Bathina M, Perciavalle RM, Bisanz K, Opferman JT. Ubiquitin-independent degradation of antiapoptotic MCL-1. Mol Cell Biol. 2010;30:3099–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Ben-Nissan G, Sharon M. Regulating the 20S proteasome ubiquitin-independent degradation pathway. Biomolecules. 2014;4:862–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Zhong Q, Gao W, Du F, Wang X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 2005;121:1085–95.

    CAS  PubMed  Google Scholar 

  71. 71.

    Warr MR, Acoca S, Liu Z, Germain M, Watson M, Blanchette M, et al. BH3-ligand regulates access of MCL-1 to its E3 ligase. FEBS Lett. 2005;579:5603–8.

    CAS  PubMed  Google Scholar 

  72. 72.

    Gomez-Bougie P, Ménoret E, Juin P, Dousset C, Pellat-Deceunynck C, Amiot M. Noxa controls Mule-dependent Mcl-1 ubiquitination through the regulation of the Mcl-1/USP9X interaction. Biochem Biophys Res Commun. 2011;413:460–4.

    CAS  PubMed  Google Scholar 

  73. 73.

    Hao Z, Duncan GS, Su Y-W, Li WY, Silvester J, Hong C, et al. The E3 ubiquitin ligase Mule acts through the ATM-p53 axis to maintain B lymphocyte homeostasis. J Exp Med. 2012;209:173–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Myant KB, Cammareri P, Hodder MC, Wills J, Von Kriegsheim A, Győrffy B, et al. HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation. EMBO Mol Med. 2017;9:181–97.

    CAS  PubMed  Google Scholar 

  75. 75.

    Subramanian A, Andronache A, Li Y-C, Wade M. Inhibition of MARCH5 ubiquitin ligase abrogates MCL1-dependent resistance to BH3 mimetics via NOXA. Oncotarget. 2016;7:15986–6002.

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Cherok E, Xu S, Li S, Das S, Meltzer WA, Zalzman M, et al. Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5-dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics. Mol Biol Cell. 2017;28:396–410.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Zhang C, Lee S, Peng Y, Bunker E, Giaime E, Shen J, et al. PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions. Curr Biol. 2014;24:1854–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Carroll RG, Hollville E, Martin SJ. Parkin sensitizes toward apoptosis induced by mitochondrial depolarization through promoting degradation of Mcl-1. Cell Rep. 2014;9:1538–53.

    CAS  PubMed  Google Scholar 

  79. 79.

    Feng C, Yang F, Wang J. FBXO4 inhibits lung cancer cell survival by targeting Mcl-1 for degradation. Cancer Gene Ther. 2017;24:342–7.

    CAS  PubMed  Google Scholar 

  80. 80.

    Ren H, Koo J, Guan B, Yue P, Deng X, Chen M, et al. The E3 ubiquitin ligases β-TrCP and FBXW7 cooperatively mediates GSK3-dependent Mcl-1 degradation induced by the Akt inhibitor API-1, resulting in apoptosis. Mol Cancer. 2013;12:146.

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Mori A, Masuda K, Ohtsuka H, Shijo M, Ariake K, Fukase K, et al. FBXW7 modulates malignant potential and cisplatin-induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1. Cancer Sci. 2018;109:3883–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Magiera MM, Mora S, Mojsa B, Robbins I, Lassot I, Desagher S. Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons. Cell Death Differ. 2013;20:281–92.

    CAS  PubMed  Google Scholar 

  83. 83.

    Shi J, Zhou Y, Huang H-C, Mitchison TJ. Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL. Cancer Res. 2011;71:4518–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Sloss O, Topham C, Diez M, Taylor S. Mcl-1 dynamics influence mitotic slippage and death in mitosis. Oncotarget. 2016;7:5176–92.

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Allan LA, Skowyra A, Rogers KI, Zeller D, Clarke PR. Atypical APC/C-dependent degradation of Mcl-1 provides an apoptotic timer during mitotic arrest. EMBO J. 2018; 37. https://doi.org/10.15252/embj.201796831.

  86. 86.

    Huang H-C, Shi J, Orth JD, Mitchison TJ. Evidence that mitotic exit is a better cancer therapeutic target than spindle assembly. Cancer Cell. 2009;16:347–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Choi YB, Harhaj EW. HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation. PLoS Pathog. 2014;10:e1004458.

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Li Z, Younger K, Gartenhaus R, Joseph AM, Hu F, Baer MR, et al. Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies. J Clin Invest. 2015;125:1081–97.

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Schwickart M, Huang X, Lill JR, Liu J, Ferrando R, French DM, et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature. 2010;463:103–7.

    CAS  PubMed  Google Scholar 

  90. 90.

    Peterson LF, Sun H, Liu Y, Potu H, Kandarpa M, Ermann M, et al. Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies. Blood. 2015;125:3588–97.

    CAS  PubMed  Google Scholar 

  91. 91.

    Zhang S, Zhang M, Jing Y, Yin X, Ma P, Zhang Z, et al. Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors. Nat Commun. 2018;9:215.

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Wang B, Xie M, Li R, Owonikoko TK, Ramalingam SS, Khuri FR, et al. Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis. Cell Death Differ. 2014;21:1160–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Amsel AD, Rathaus M, Kronman N, Cohen HY. Regulation of the proapoptotic factor Bax by Ku70-dependent deubiquitylation. Proc Natl Acad Sci USA. 2008;105:5117–22.

    CAS  PubMed  Google Scholar 

  94. 94.

    Clohessy JG, Zhuang J, Brady HJM. Characterisation of Mcl-1 cleavage during apoptosis of haematopoietic cells. Br J Haematol. 2004;125:655–65.

    CAS  PubMed  Google Scholar 

  95. 95.

    Han J, Goldstein LA, Gastman BR, Rabinovitz A, Rabinowich H. Disruption of Mcl-1·Bim complex in granzyme B-mediated mitochondrial apoptosis. J Biol Chem. 2005;280:16383–92.

    CAS  PubMed  Google Scholar 

  96. 96.

    Weng C, Li Y, Xu D, Shi Y, Tang H. Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing Ligand (TRAIL)-induced apoptosis in Jurkat leukemia T Cells. J Biol Chem. 2005;280:10491–10500.

    CAS  PubMed  Google Scholar 

  97. 97.

    Fan F, Tonon G, Bashari MH, Vallet S, Antonini E, Goldschmidt H, et al. Targeting Mcl-1 for multiple myeloma (MM) therapy: drug-induced generation of Mcl-1 fragment Mcl-1128–350 triggers MM cell death via c-Jun upregulation. Cancer Lett. 2014;343:286–94.

    CAS  PubMed  Google Scholar 

  98. 98.

    Herrant M, Jacquel A, Marchetti S, Belhacène N, Colosetti P, Luciano F, et al. Cleavage of Mcl-1 by caspases impaired its ability to counteract Bim-induced apoptosis. Oncogene. 2004;23:7863–73.

    CAS  PubMed  Google Scholar 

  99. 99.

    Thomas MP, Liu X, Whangbo J, McCrossan G, Sanborn KB, Basar E, et al. Apoptosis triggers specific, rapid, and global mRNA decay with 3′ uridylated intermediates degraded by DIS3L2. Cell Rep. 2015;11:1079–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463:899–905.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Moshynska O, Sankaran K, Pahwa P, Saxena A. Prognostic significance of a short sequence insertion in the MCL-1 promoter in chronic lymphocytic leukemia. J Natl Cancer Inst. 2004;96:673–82.

    CAS  PubMed  Google Scholar 

  102. 102.

    Fernández-Marrero Y, Spinner S, Kaufmann T, Jost PJ. Survival control of malignant lymphocytes by anti-apoptotic MCL-1. Leukemia. 2016;30:2152–9.

    PubMed  Google Scholar 

  103. 103.

    Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res. 2017;45:D777–D783.

    CAS  Google Scholar 

  104. 104.

    Mazumder S, Choudhary GS, Al-Harbi S, Almasan A. Mcl-1 Phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B cells. Cancer Res. 2012;72:3069–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Mancinelli R, Carpino G, Petrungaro S, Mammola CL, Tomaipitinca L, Filippini A, et al. Multifaceted roles of GSK-3 in cancer and autophagy-related diseases. Oxid Med Cell Longev. 2017;2017:4629495.

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Koo J, Yue P, Deng X, Khuri FR, Sun S-Y. mTOR complex 2 stabilizes Mcl-1 protein by suppressing its glycogen synthase kinase 3-dependent and SCF-FBXW7-mediated degradation. Mol Cell Biol. 2015;35:2344–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Tong J, Tan S, Zou F, Yu J, Zhang L. FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation. Oncogene. 2017;36:787–96.

    CAS  PubMed  Google Scholar 

  108. 108.

    He L, Torres-Lockhart K, Forster N, Ramakrishnan S, Greninger P, Garnett MJ, et al. Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma. Cancer Discov. 2013;3:324–37.

    CAS  PubMed  Google Scholar 

  109. 109.

    He C, Sun J, Liu C, Jiang Y, Hao Y. Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin. Clin Epigenetics. 2019; 11. https://doi.org/10.1186/s13148-018-0605-x.

  110. 110.

    He M, Chaurushiya MS, Webster JD, Kummerfeld S, Reja R, Chaudhuri S, et al. Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1. Science. 2019;364:283–5.

    CAS  PubMed  Google Scholar 

  111. 111.

    Ishii N, Araki K, Yokobori T, Gantumur D, Yamanaka T, Altan B, et al. Reduced FBXW7 expression in pancreatic cancer correlates with poor prognosis and chemotherapeutic resistance via accumulation of MCL1. Oncotarget. 2017;8:112636–46.

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Maddocks K, Wei L, Rozewski D, Jiang Y, Zhao Y, Adusumilli M, et al. Reduced occurrence of tumor flare with flavopiridol followed by combined flavopiridol and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL). Am J Hematol. 2015;90:327–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Mitri Z, Karakas C, Wei C, Briones B, Simmons H, Ibrahim N, et al. A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer. Invest N. Drugs. 2015;33:890–4.

    CAS  Google Scholar 

  114. 114.

    Karp JE, Smith BD, Resar LS, Greer JM, Blackford A, Zhao M, et al. Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood. 2011;117:3302–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Kadia TM, Kantarjian HM, Konopleva M. Myeloid cell leukemia-1 dependence in acute myeloid leukemia: a novel approach to patient therapy. Oncotarget 2019;10:1250–65.

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Senichkin VV, Kopeina GS, Prokhorova EA, Zamaraev AV, Lavrik IN, Zhivotovsky B. Modulation of Mcl-1 transcription by serum deprivation sensitizes cancer cells to cisplatin. Biochim Biophys Acta Gen Subj. 2018;1862:557–66.

    CAS  PubMed  Google Scholar 

  117. 117.

    Kopeina GS, Senichkin VV, Zhivotovsky B. Caloric restriction—a promising anti-cancer approach: from molecular mechanisms to clinical trials. Biochim Biophys Acta Rev Cancer 2017;1867:29–41.

    CAS  PubMed  Google Scholar 

  118. 118.

    Elgendy M, Cirò M, Hosseini A, Weiszmann J, Mazzarella L, Ferrari E, et al. Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating the PP2A-GSK3β-MCL-1 axis. Cancer Cell. 2019;35:798–815.e5.

    CAS  PubMed  Google Scholar 

  119. 119.

    Rahmani M, Davis EM, Bauer C, Dent P, Grant S. Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem. 2005;280:35217–27.

    CAS  PubMed  Google Scholar 

  120. 120.

    Wang R, Xia L, Gabrilove J, Waxman S, Jing Y. Sorafenib inhibition of Mcl-1 accelerates ATRA-induced apoptosis in differentiation-responsive AML cells. Clin Cancer Res. 2016;22:1211–21.

    CAS  PubMed  Google Scholar 

  121. 121.

    Gomez-Bougie P, Wuillème-Toumi S, Ménoret E, Trichet V, Robillard N, Philippe M, et al. Noxa up-regulation and Mcl-1 cleavage are associated to apoptosis induction by bortezomib in multiple myeloma. Cancer Res. 2007;67:5418–24.

    CAS  PubMed  Google Scholar 

  122. 122.

    Lamothe B, Wierda WG, Keating MJ, Gandhi V. Carfilzomib triggers cell death in chronic lymphocytic leukemia by inducing proapoptotic and endoplasmic reticulum stress responses. Clin Cancer Res. 2016;22:4712–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Bhattacharyya A, Chattopadhyay R, Hall EH, Mebrahtu ST, Ernst PB, Crowe SE. Mechanism of hypoxia-inducible factor 1α-mediated Mcl1 regulation in Helicobacter pylori-infected human gastric epithelium. Am J Physiol Gastrointest Liver Physiol. 2010;299. https://doi.org/10.1152/ajpgi.00372.2010.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Townsend KJ, Zhou P, Qian L, Bieszczad CK, Lowrey CH, Yen A, et al. Regulation of MCL1 through a serum response factor/Elk-1-mediated mechanism links expression of a viability-promoting member of the BCL2 family to the induction of hematopoietic cell differentiation. J Biol Chem. 1999;274:1801–13.

    CAS  PubMed  Google Scholar 

  125. 125.

    Day BW, Stringer BW, Spanevello MD, Charmsaz S, Jamieson PR, Ensbey KS, et al. ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1. Neuro Oncol. 2011;13:1202–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Hu J, Dang N, Menu E, De Bruyne E, De Bryune E, Xu D, et al. Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition. Blood. 2012;119:826–37.

    CAS  PubMed  Google Scholar 

  127. 127.

    Chen Y-J, Huang C-H, Shi Y-J, Lee Y-C, Wang L-J, Chang L-S. The suppressive effect of arsenic trioxide on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 expression induces apoptosis in human leukemia cells. Toxicol Appl Pharm. 2018;358:43–55.

    CAS  Google Scholar 

  128. 128.

    Isomoto H, Kobayashi S, Werneburg NW, Bronk SF, Guicciardi ME, Frank DA, et al. Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology. 2005;42:1329–38.

    CAS  PubMed  Google Scholar 

  129. 129.

    Becker TM, Boyd SC, Mijatov B, Gowrishankar K, Snoyman S, Pupo GM, et al. Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Oncogene. 2014;33:1158–66.

    CAS  PubMed  Google Scholar 

  130. 130.

    Dong L, Jiang CC, Thorne RF, Croft A, Yang F, Liu H, et al. Ets-1 mediates upregulation of Mcl-1 downstream of XBP-1 in human melanoma cells upon ER stress. Oncogene. 2011;30:3716.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Ricci MS, Kim S-H, Ogi K, Plastaras JP, Ling J, Wang W, et al. Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. Cancer Cell. 2007;12:66–80.

    CAS  PubMed  Google Scholar 

  132. 132.

    Labisso WL, Wirth M, Stojanovic N, Stauber RH, Schnieke A, Schmid RM, et al. MYC directs transcription of MCL1 and eIF4E genes to control sensitivity of gastric cancer cells toward HDAC inhibitors. Cell Cycle. 2012;11:1593–602.

    CAS  PubMed  Google Scholar 

  133. 133.

    Schacter JL, Henson ES, Gibson SB. Estrogen regulation of anti-apoptotic Bcl-2 family member Mcl-1 expression in breast cancer cells. PLoS ONE. 2014;9:e100364.

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Rosato RR, Almenara JA, Kolla SS, Maggio SC, Coe S, Giménez MS, et al. Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions. Mol Cancer Ther. 2007;6:692–702.

    CAS  PubMed  Google Scholar 

  135. 135.

    Akgul C, Turner PC, White MRH, Edwards* SW. Functional analysis of the human MCL-1 gene. Cell Mol Life Sci. 2000;57:684–91.

    CAS  PubMed  Google Scholar 

  136. 136.

    Wang S-H, Zhang W-J, Wu X-C, Weng M-Z, Zhang M-D, Cai Q, et al. The lncRNA MALAT1 functions as a competing endogenous RNA to regulate MCL-1 expression by sponging miR-363-3p in gallbladder cancer. J Cell Mol Med. 2016;20:2299–308.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Wang H, Wang L, Zhang G, Lu C, Chu H, Yang R, et al. MALAT1/miR-101-3p/MCL1 axis mediates cisplatin resistance in lung cancer. Oncotarget. 2018;9:7501–12.

    PubMed  Google Scholar 

  138. 138.

    Stamato MA, Juli G, Romeo E, Ronchetti D, Arbitrio M, Caracciolo D, et al. Inhibition of EZH2 triggers the tumor suppressive miR-29b network in multiple myeloma. Oncotarget. 2017;8:106527–37.

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Liu B, Cao W, Xue J. LncRNA ANRIL protects against oxygen and glucose deprivation (OGD)-induced injury in PC-12 cells: potential role in ischaemic stroke. Artif Cells Nanomed Biotechnol. 2019;47:1384–95.

    CAS  PubMed  Google Scholar 

  140. 140.

    Chen D, Lu X, Yang F, Xing N. Circular RNA circHIPK3 promotes cell proliferation and invasion of prostate cancer by sponging miR-193a-3p and regulating MCL1 expression. Cancer Manag Res. 2019;11:1415–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Pan Y, Zhang Y, Liu W, Huang Y, Shen X, Jing R, et al. LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via miR-29b-3p. Cell Death Dis. 2019;10:106.

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Yin D, Li Y, Fu C, Feng Y. Pro-angiogenic role of LncRNA HULC in microvascular endothelial cells via sequestrating miR-124. Cell Physiol Biochem. 2018;50:2188–202.

    CAS  PubMed  Google Scholar 

  143. 143.

    Huang Y, Luo H, Li F, Yang Y, Ou G, Ye X, et al. LINC00152 down-regulated miR-193a-3p to enhance MCL1 expression and promote gastric cancer cells proliferation. Biosci Rep. 2018;38:BSR20171607.

  144. 144.

    Chen P, Fang X, Xia B, Zhao Y, Li Q, Wu X. Long noncoding RNA LINC00152 promotes cell proliferation through competitively binding endogenous miR-125b with MCL-1 by regulating mitochondrial apoptosis pathways in ovarian cancer. Cancer Med. 2018;7:4530–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Han Y, Wu N, Jiang M, Chu Y, Wang Z, Liu H, et al. Long non-coding RNA MYOSLID functions as a competing endogenous RNA to regulate MCL-1 expression by sponging miR-29c-3p in gastric cancer. Cell Prolif. 2019;52:e12678.

  146. 146.

    Li X, Yu M, Chen L, Sun T, Wang H, Zhao L, et al. LncRNA PMS2L2 protects ATDC5 chondrocytes against lipopolysaccharide-induced inflammatory injury by sponging miR-203. Life Sci. 2019;217:283–92.

    CAS  PubMed  Google Scholar 

  147. 147.

    Zhou B, Li L, Li Y, Sun H, Zeng C. Long noncoding RNA SNHG12 mediates doxorubicin resistance of osteosarcoma via miR-320a/MCL1 axis. Biomed Pharmacother. 2018;106:850–7.

    CAS  PubMed  Google Scholar 

  148. 148.

    Du Q, Hu B, Feng Y, Wang Z, Wang X, Zhu D, et al. circOMA1-mediated miR-145-5p suppresses tumor growth of nonfunctioning pituitary adenomas by targeting TPT1. J Clin Endocrinol Metab. 2019;104:2419–34.

    PubMed  Google Scholar 

  149. 149.

    Wu Q, Yang F, Yang Z, Fang Z, Fu W, Chen W, et al. Long noncoding RNA PVT1 inhibits renal cancer cell apoptosis by up-regulating Mcl-1. Oncotarget. 2017;8:101865–75.

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Zheng X-L, Zhang Y-Y, Lv W-G. Long noncoding RNA ITGB1 promotes migration and invasion of clear cell renal cell carcinoma by downregulating Mcl-1. Eur Rev Med Pharm Sci. 2019;23:1996–2002.

    Google Scholar 

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Acknowledgements

This work was supported by a grant from the Russian Science Foundation (17-75-20102). The work in the authors’ laboratories is supported by grants from the Russian Foundation for Basic Research (19-015-00332, 18-29-09005), the Stockholm (181301) and Swedish (190345) Cancer Societies.

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Senichkin, V.V., Streletskaia, A.Y., Gorbunova, A.S. et al. Saga of Mcl-1: regulation from transcription to degradation. Cell Death Differ 27, 405–419 (2020). https://doi.org/10.1038/s41418-019-0486-3

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