Getting away with murder: How does the BCL-2 family of proteins kill with immunity?

Annals of the New York Academy of Sciences

Volumn 1285, Issue 1, 2013, Pages 59-79

  Renault, Thibaud T ^a   Chipuk, Jerry E ^a  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

Author keywords

Apoptosis; BCL 2 family; Immunity; Mitochondria

Indexed keywords

APOPTOSIS REGULATORY PROTEIN; AUTOIMMUNE REGULATOR PROTEIN; B LYMPHOCYTE RECEPTOR; BCL2 RELATED PROTEIN A1; BECLIN 1; BH3 PROTEIN; BIM PROTEIN; CASPASE 8; CD4 ANTIGEN; CD8 ANTIGEN; INTERLEUKIN 1BETA; MESSENGER RNA; MICRORNA; MYC PROTEIN; NUCLEOLIN; PROTEIN BAD; PROTEIN BAK; PROTEIN BAX; PROTEIN BCL 2; PROTEIN BCL W; PROTEIN BCL XL; PROTEIN BID; PROTEIN MCL 1; PROTEIN NOXA; PROTEIN P53; PUMA PROTEIN; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR FKHRL1; TUMOR NECROSIS FACTOR RECEPTOR; TUMOR SUPPRESSOR PROTEIN;

ALTERNATIVE RNA SPLICING; APOPTOSIS; ARTICLE; AUTOPHAGY; B CELL LYMPHOMA; B LYMPHOCYTE; CARCINOGENESIS; CELL DIFFERENTIATION; CELL MATURATION; CELL PHAGOCYTOSIS; CELL SURVIVAL; CELLULAR DISTRIBUTION; CHANNEL GATING; DEAMINATION; ENZYMATIC DEGRADATION; ENZYME ACTIVATION; ENZYME INDUCTION; HEMATOPOIETIC STEM CELL; HUMAN; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOREGULATION; INTRACELLULAR SIGNALING; MACROPHAGE; MEMORY CELL; METABOLISM; MITOCHONDRIAL DYNAMICS; MITOCHONDRIAL MEMBRANE; NEUTROPHIL; NONHUMAN; OLIGOMERIZATION; ONCOGENE C MYC; PRE B LYMPHOCYTE; PRE T LYMPHOCYTE; PROTEIN CLEAVAGE; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FAMILY; PROTEIN FUNCTION; PROTEIN METABOLISM; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; PROTEIN STABILITY; PROTEIN TARGETING; SPONTANEOUS MUTATION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; UBIQUITINATION;

EID: 84878205750     PISSN: 00778923     EISSN: 17496632     Source Type: Book Series    
DOI: 10.1111/nyas.12045     Document Type: Article

References (175)

1. Meier, P., A. Finch & G. Evan 2000. Apoptosis in development. Nature 407: 796-801.
2. Sprent, J. & D.F. Tough 2001. T cell death and memory. Science 293: 245-248.
3. Murphy, K. 2011. Janeway's Immunobiology (Immunobiology: the Immune System). 8th ed. New York: Garland Science.
4. Huse, M. 2009. The T-cell-receptor signaling network. J. Cell. Sci. 122(Pt 9): 1269-1273.
5. Zemlin, M., R.L. Schelonka, K. Bauer & H.W. Schroeder Jr. 2002. Regulation and chance in the ontogeny of B and T cell antigen receptor repertoires. Immunol. Res. 26: 265-278.
6. Opferman, J.T. 2007. Life and death during hematopoietic differentiation. Curr. Opin. Immunol. 19: 497-502.
7. Hernandez, J.B., R.H. Newton & C.M. Walsh 2010. Life and death in the thymus-cell death signaling during T cell development. Curr. Opin. Cell. Biol. 22: 865-871.
8. Corfe, S.A. & C.J. Paige 2012. The many roles of IL-7 in B cell development; mediator of survival, proliferation and differentiation. Semin. Immunol. 24: 198-208.
9. Hardy, R.R. & K. Hayakawa 2001. B cell development pathways. Annu. Rev. Immunol. 19: 595-621.
10. Häcker, G. 2000. The morphology of apoptosis. Cell. Tissue Res. 301: 5-17.
11. Fadok, V.A. 1999. Clearance: the last and often forgotten stage of apoptosis. J. Mammary Gland. Biol. Neoplasia. 4: 203-211.
12. Tsujimoto, Y., J. Cossman, E. Jaffe & C.M. Croce 1985. Involvement of the bcl-2 gene in human follicular lymphoma. Science 228: 1440-1443.
13. Vaux, D.L., S. Cory & J.M. Adams 1988. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335: 440-442.
14. Egle, A., A.W. Harris, P. Bouillet & S. Cory 2004. Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc. Natl. Acad. Sci. U.S.A. 101: 6164-6169.
15. Hemann, M.T., A. Bric, J. Teruya-Feldstein, et al. 2005. Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 436: 807-811.
16. Hipfner, D.R. & S.M. Cohen 2004. Connecting proliferation and apoptosis in development and disease. Nat. Rev. Mol. Cell Biol. 5: 805-815.
17. Cheng, E.H., M.C. Wei, S. Weiler, et al. 2001. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell 8: 705-711.
18. Certo, M., V.D.G. Moore, M. Nishino, et al. 2006. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9: 351-365.
19. Liu, X., C.N. Kim, J. Yang, et al. 1996. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86: 147-157.
20. Kluck, R.M., E. Bossy-Wetzel, D.R. Green & D.D. Newmeyer 1997. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275: 1132-1136.
21. Chipuk, J.E. & D.R. Green 2008. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 18: 157-164.
22. Kuwana, T., M.R. Mackey, G. Perkins, et al. 2002. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111: 331-342.
23. Chipuk, J.E., G.P. McStay, A. Bharti, et al. 2012. Sphingolipid Metabolism Cooperates with BAK and BAX to Promote the Mitochondrial Pathway of Apoptosis. Cell 148: 988-1000.
24. Ke, F., A. Voss, J.B. Kerr, et al. 2012. BCL-2 family member BOK is widely expressed but its loss has only minimal impact in mice. Cell Death Differ. 19: 915-925.
25. Sattler, M., H. Liang, D. Nettesheim, et al. 1997. Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science 275: 983-986.
26. Gavathiotis, E., M. Suzuki, M.L. Davis, et al. 2008. BAX activation is initiated at a novel interaction site. Nature 455: 1076-1081.
27. George, N.M., J.J.D. Evans, X. Luo 2007. A three-helix homo-oligomerization domain containing BH3 and BH1 is responsible for the apoptotic activity of Bax. Genes. Dev. 21: 1937-1948.
28. Dewson, G., T. Kratina, H.W. Sim, et al. 2008. To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3: groove interactions. Mol. Cell 30: 369-380.
29. Dewson, G., T. Kratina, P. Czabotar, et al. 2009. Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices. Mol. Cell 36: 696-703.
30. Yin, X.M., Z.N. Oltvai & S.J. Korsmeyer 1994. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369: 321-323.
31. Sedlak, T.W., Z.N. Oltvai, E. Yang, et al. 1995. Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc. Natl. Acad. Sci. USA 92: 7834-7838.
32. Meijerink, J.P., E.J. Mensink, K. Wang, et al. 1998. Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood 91: 2991-2997.
33. Strasser, A., A.W. Harris & S. Cory 1991. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell 67: 889-899.
34. Strasser, A., S. Whittingham, D.L. Vaux, et al. 1991. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc. Natl. Acad. Sci. USA 88: 8661-8665.
35. Veis, D.J., C.M. Sorenson, J.R. Shutter & S.J. Korsmeyer 1993. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75: 229-240.
36. Veis, D.J., C.L. Sentman, E.A. Bach & S.J. Korsmeyer 1993. Expression of the Bcl-2 protein in murine and human thymocytes and in peripheral T lymphocytes. J. Immunol. 151: 2546-2554.
37. Nuñez, G., D. Hockenbery, T.J. McDonnell, et al. 1991. Bcl-2 maintains B cell memory. Nature 353: 71-73.
38. Bouillet, P., D. Metcalf, D.C. Huang, et al. 1999. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286: 1735-1738.
39. Nakayama, K., K. Nakayama, I. Negishi, et al. 1993. Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science 261: 1584-1588.
40. Bouillet, P., S. Cory, L.C. Zhang, et al. 2001. Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. Dev. Cell 1: 645-653.
41. Bouillet, P., J.F. Purton, D.I. Godfrey, et al. 2002. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415: 922-926.
42. Mérino, D., M. Giam, P.D. Hughes, et al. 2009. The role of BH3-only protein Bim extends beyond inhibiting Bcl-2-like prosurvival proteins. J. Cell Biol. 186: 355-362.
43. Mérino, D. & P. Bouillet 2009. The Bcl-2 family in autoimmune and degenerative disorders. Apoptosis 14: 570-583.
44. Kirschnek, S., S. Ying, S.F. Fischer, et al. 2005. Phagocytosis-Induced Apoptosis in Macrophages Is Mediated by Up-Regulation and Activation of the Bcl-2 Homology Domain 3-Only Protein Bim. J. Immunol. 174: 671-679.
45. Rinkenberger, J.L., S. Horning, B. Klocke, et al. 2000. Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes. Dev. 14: 23-27.
46. Opferman, J.T., A. Letai, C. Beard, et al. 2003. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426: 671-676.
47. Campbell, K.J., D.H.D. Gray, N. Anstee, et al. 2012. Elevated Mcl-1 inhibits thymocyte apoptosis and alters thymic selection. Cell Death Differ. 19: 1962-1971.
48. Vikstrom, I., S. Carotta, K. Lüthje, et al. 2010. Mcl-1 is essential for germinal center formation and B cell memory. Science 330: 1095-1099.
49. Opferman, J.T., H. Iwasaki, C.C. Ong, et al. 2005. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307: 1101-1104.
50. Dzhagalov, I., A.S. John & Y-W. He 2007. The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood 109: 1620-1626.
51. Glaser, S.P., E.F. Lee, E. Trounson, et al. 2012. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes. Dev. 26: 120-125.
52. Mandal, M., C. Borowski, T. Palomero, et al. 2005. The BCL2A1 gene as a pre-T cell receptor-induced regulator of thymocyte survival. J. Exp. Med. 201: 603-614.
53. Hamasaki, A., F. Sendo, K. Nakayama, et al. 1998. Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene. J. Exp. Med. 188: 1985-1992.
54. Ma, A., J.C. Pena, B. Chang, et al. 1995. Bclx regulates the survival of double-positive thymocytes. Proc. Natl. Acad. Sci. U.S.A. 92: 4763-4767.
55. Lindsten, T., A.J. Ross, A. King, et al. 2000. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol. Cell. 6: 1389-1399.
56. Renault, T.T. & S. Manon 2011. Bax: addressed to kill. Biochimie 93: 1379-1391.
57. Knudson, C.M., K.S. Tung, W.G. Tourtellotte, et al. 1995. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270: 96-99.
58. Rathmell, J.C., T. Lindsten, W-X. Zong, et al. 2002. Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat. Immunol. 3: 932-939.
59. Hsu, S.Y., A. Kaipia, E. McGee, et al. 1997. Bok is a pro-apoptotic Bcl-2 protein with restricted expression in reproductive tissues and heterodimerizes with selective anti-apoptotic Bcl-2 family members. Proc. Natl. Acad. Sci. U.S.A. 94: 12401-12406.
60. Michalak, E.M., E.S. Jansen, L. Happo, et al. 2009. Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis. Cell Death Differ. 16: 684-696.
61. Elgendy, M., C. Sheridan, G. Brumatti & S.J. Martin 2011. Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Mol. Cell 42: 23-35.
62. Villunger, A., C. Scott, P. Bouillet & A. Strasser 2003. Essential role for the BH3-only protein Bim but redundant roles for Bax, Bcl-2, and Bcl-w in the control of granulocyte survival. Blood 101: 2393-2400.
63. Kirschnek, S., J. Vier, S. Gautam, et al. 2011. Molecular analysis of neutrophil spontaneous apoptosis reveals a strong role for the pro-apoptotic BH3-only protein Noxa. Cell Death Differ. 18: 1805-1814.
64. Garrison, S.P., D.C. Phillips, J.R. Jeffers, et al. 2012. Genetically defining the mechanism of Puma- and Bim-induced apoptosis. Cell Death Differ. 19: 642-649.
65. Erlacher, M., V. Labi, C. Manzl, et al. 2006. Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. J. Exp. Med. 203: 2939-2951.
66. Villunger, A., E.M. Michalak, L. Coultas, et al. 2003. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302: 1036-1038.
67. Gray, D.H.D., F. Kupresanin, S.P. Berzins, et al. 2012. The BH3-only proteins Bim and Puma cooperate to impose deletional tolerance of organ-specific antigens. Immunity 37: 451-462.
68. Zhan, Y., Y. Zhang, D. Gray, et al. 2011. Defects in the Bcl-2-regulated apoptotic pathway lead to preferential increase of CD25 low Foxp3+ anergic CD4+ T cells. J. Immunol. 187: 1566-1577.
69. Labi V, M. Erlacher, S. Kiessling, et al. 2008. Loss of the BH3-only protein Bmf impairs B cell homeostasis and accelerates γ irradiation-induced thymic lymphoma development. J. Exp. Med. 205: 641-655.
70. Ploner, C., J. Rainer, H. Niederegger, et al. 2008. The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia. Leukemia 22: 370-377.
71. Baumgartner, F., C. Woess, V. Pedit, et al. 2012. Minor cell-death defects but reduced tumor latency in mice lacking the BH3-only proteins Bad and Bmf. Mar 19. DOI: 10.1038/onc.2012.78. [Epub ahead of print].
72. Siebenlist, U., K. Brown & E. Claudio 2005. Control of lymphocyte development by nuclear factor-kappaB. Nat. Rev. Immunol. 5: 435-445.
73. Hayden, M.S., A.P. West, S. Ghosh 2006. NF-kappaB and the immune response. Oncogene 25: 6758-6780.
74. Kucharczak, J., M.J. Simmons, Y. Fan & C. Gélinas 2003. To be, or not to be: NF-kappaB is the answer-role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene 22: 8961-8982.
75. Voll, R.E., E. Jimi, R.J. Phillips, et al. 2000. NF-kappa B activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13: 677-689.
76. Zheng, Y., M. Vig, J. Lyons, et al. 2003. Combined deficiency of p50 and cRel in CD4+ T cells reveals an essential requirement for nuclear factor κB in regulating mature T cell survival and in vivo function. J. Exp. Med. 197: 861-874.
77. Miyashita, T. & J.C. Reed 1995. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80: 293-299.
78. Oda, E., R. Ohki, H. Murasawa, et al. 2000. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288: 1053-1058.
79. Nakano, K. & K.H. Vousden 2001. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7: 683-694.
80. Mathai, J.P., M. Germain, R.C. Marcellus & G.C. Shore 2002. Induction and endoplasmic reticulum location of BIK/NBK in response to apoptotic signaling by E1A and p53. Oncogene 21: 2534-2544.
81. Sax, J.K., P. Fei, M.E. Murphy, et al. 2002. BID regulation by p53 contributes to chemosensitivity. Nat. Cell Biol. 4: 842-849.
82. Miyashita, T., S. Krajewski, M. Krajewska, et al. 1994. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9: 1799-1805.
83. Chipuk, J.E., T. Kuwana, L. Bouchier-Hayes, et al. 2004. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303: 1010-1014.
84. Leu, JI-J., P. Dumont, M. Hafey, et al. 2004. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat. Cell Biol. 6: 443-450.
85. Mihara, M., S. Erster, A. Zaika, et al. 2003. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 11: 577-590.
86. Stadanlick, J.E., Z. Zhang, S-Y. Lee, et al. 2011. Developmental arrest of T cells in Rpl22-deficient mice is dependent upon multiple p53 effectors. J. Immunol. 187: 664-675.
87. Mitchell, K.O., M.S. Ricci, T. Miyashita, et al. 2000. Bax is a transcriptional target and mediator of c-myc-induced apoptosis. Cancer Res. 60: 6318-6325.
88. Eischen, C.M., D. Woo, M.F. Roussel & J.L. Cleveland 2001. Apoptosis triggered by Myc-induced suppression of Bcl-XL or Bcl-2 is bypassed during lymphomagenesis. Mol. Cell Biol. 21: 5063-5070.
89. Dijkers, P.F., R.H. Medema, J.W. Lammers, et al. 2000. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr. Biol. 10: 1201-1204.
90. Jurado, S., K. Gleeson, K. O'Donnell, et al. 2012. The Zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim. J. Exp. Med. 209: 1629-1639.
91. Milot, E. & J.G. Filep 2011. Regulation of neutrophil survival/apoptosis by Mcl-1. Sci. World J. 11: 1948-1962.
92. Allen, J.C., F. Talab, M. Zuzel, et al. 2011. c-Abl regulates Mcl-1 gene expression in chronic lymphocytic leukemia cells. Blood 117: 2414-2422.
93. O'Connor, L., A. Strasser, L.A. O'Reilly, et al. 1998. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 17: 384-395.
94. Adachi, M., X. Zhao & K. Imai 2005. Nomenclature of dynein light chain-linked BH3-only protein Bim isoforms. Cell Death and Differen. 12: 192-193.
95. Liu, L., J. Chen, J. Zhang, et al. 2007. Overexpression of BimSs3, the novel isoform of Bim, can trigger cell apoptosis by inducing cytochrome c release from mitochondria. Acta Biochim. Pol. 54: 603-610.
96. Boise, L.H., M. Gonzalez-Garcia, C.E. Postema, et al. 1993. Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74: 597-608.
97. Oltvai, Z.N., C.L. Milliman & S.J. Korsmeyer 1993. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74: 609-619.
98. Otake, Y., S. Soundararajan, T.K. Sengupta, et al. 2007 Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA. Blood 109: 3069-3075.
99. Ventura, A., A.G. Young, M.M. Winslow, et al. 2008. Targeted deletion reveals essential and overlapping functions of the miR-17∼92 family of miRNA clusters. Cell 132: 875-886.
100. Cimmino, A., G.A. Calin, M. Fabbri, et al. 2005. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl. Acad. Sci. USA 102: 13944-13949.
101. Calin, G.A., A. Cimmino, M. Fabbri, et al. 2008. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc. Natl. Acad. Sci. USA. 105: 5166-5171.
102. Wu, Z., H. Lu, J. Sheng & L. Li 2012. Inductive microRNA-21 impairs anti-mycobacterial responses by targeting IL-12 and Bcl-2. FEBS Letters [Internet]. Available from: http://www.sciencedirect.com/science/article/pii/S0014579312004681 [accessed on 23 July 2012].
103. Lindsay, M.A. 2008. microRNAs and the immune response. Trends Immunol. 29: 343-351.
104. Lima, R.T., S. Busacca, G.M. Almeida, et al. 2011. MicroRNA regulation of core apoptosis pathways in cancer. Eur. J. Cancer 47: 163-174.
105. Deng, X., P. Ruvolo, B. Carr & W.S. May 2000. Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases. Proc. Natl. Acad. Sci. USA 97: 1578-1583.
106. Yamamoto, K., H. Ichijo & S.J. Korsmeyer 1999. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G2/M. Mol. Cell Biol. 19: 8469-8478.
107. Deng, X., F. Gao, T. Flagg & W.S. May 2004. Mono- and multisite phosphorylation enhances Bcl2's antiapoptotic function and inhibition of cell cycle entry functions. Proc. Natl. Acad. Sci. USA 101: 153-158.
108. Dimmeler, S., K. Breitschopf, J. Haendeler & A.M. Zeiher 1999. Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation: a link between the apoptosome and the proteasome pathway. J. Exp. Med. 1189: 1815-1822.
109. Breitschopf, K., J. Haendeler, P. Malchow, et al. 2000. Posttranslational modification of Bcl-2 facilitates its proteasome-dependent degradation: molecular characterization of the involved signaling pathway. Mol. Cell. Biol. 20: 1886-1896.
110. Wang, Y-Y, X. Deng, L. Xu, et al. 2008. Bcl2 enhances induced hematopoietic differentiation of murine embryonic stem cells. Exp. Hematol. 36: 128-139.
111. Luciano, F., A. Jacquel, P. Colosetti, et al. 2003. Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function. Oncogene 22: 6785-6793.
112. Ley, R., K.E. Ewings, K. Hadfield, et al. 2004. Extracellular signal-regulated kinases 1/2 are serum-stimulated "BimEL kinases" that bind to the BH3-only protein BimEL causing its phosphorylation and turnover. J. Biol. Chem. 279: 8837-8847.
113. O'Reilly, L.A., E.A. Kruse, H. Puthalakath, et al. 2009. MEK/ERK-mediated phosphorylation of bim is required to ensure survival of T and B lymphocytes during mitogenic stimulation. J. Immunol. 183: 261-269.
114. Paterson, A., C.I. Mockridge, J.E. Adams, et al. 2012. Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia. Blood 119: 1726-1736.
115. Lizcano, J.M., N. Morrice & P. Cohen 2000. Regulation of BAD by cAMP-dependent protein kinase is mediated via phosphorylation of a novel site, Ser155. Biochem. J. 349(Pt 2): 547-557.
116. Virdee, K., P.A. Parone & A.M. Tolkovsky 2000. Phosphorylation of the pro-apoptotic protein BAD on serine 155, a novel site, contributes to cell survival. Curr. Biol. 10: 1151-1154.
117. Tan, Y., M.R. Demeter, H. Ruan & M.J. Comb 2000. BAD Ser-155 phosphorylation regulates BAD/Bcl-XL interaction and cell survival. J. Biol. Chem. 275: 25865-25869.
118. Harada, H., B. Becknell, M. Wilm, et al. 1999. Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol. Cell 3: 413-422.
119. Datta, S.R., H. Dudek, X. Tao, et al. 1997. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91: 231-241.
120. Li, H., H. Zhu, C.J. Xu & J. Yuan 1998. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491-501.
121. Zha, J., S. Weiler, K.J. Oh, et al. 2000. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 290: 1761-1765.
122. Lovell, J.F., L.P. Billen, S. Bindner, et al. 2008. Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 135: 1074-1084.
123. Boya, P., K. Andreau, D. Poncet, et al. 2003. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J. Exp. Med. 197: 1323-1334.
124. Chen, M., H. He, S. Zhan, et al. 2001. Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. J. Biol. Chem 276: 30724-30728.
125. Stoka, V., B. Turk, S.L. Schendel, et al. 2001. Lysosomal protease pathways to apoptosis. Cleavage of bid, not pro-caspases, is the most likely route. J. Biol. Chem. 276: 3149-31457.
126. Cirman, T., K. Oresić, G.D. Mazovec, et al. 2004. Selective disruption of lysosomes in HeLa cells triggers apoptosis mediated by cleavage of Bid by multiple papain-like lysosomal cathepsins. J. Biol. Chem. 279: 3578-3587.
127. Sutton, V.R., J.E. Davis, M. Cancilla, et al. 2000. Initiation of apoptosis by granzyme B requires direct cleavage of bid, but not direct granzyme B-mediated caspase activation. J. Exp. Med. 192: 1403-1414.
128. Campbell, K.J., M.L. Bath, M.L. Turner, et al. 2010. Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance. Blood 116: 3197-3207.
129. Michels, J., J.W. O'Neill, C.L. Dallman, et al. 2004. Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Oncogene 23: 4818-4827.
130. Cheng, E.H., D.G. Kirsch, et al. 1997. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278: 1966-1968.
131. Clem, R.J., E.H. Cheng, C.L. Karp, et al. 1998. Modulation of cell death by Bcl-XL through caspase interaction. Proc. Natl. Acad. Sci. U.S.A. 95: 554-559.
132. Kirsch, D.G., A. Doseff, B.N. Chau, et al. 1999. Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c. J. Biol. Chem. 274: 21155-21161.
133. Basañez, G., J. Zhang, B.N. Chau, et al. 2001. Pro-apoptotic cleavage products of Bcl-xL form cytochrome c-conducting pores in pure lipid membranes. J. Biol. Chem. 276: 31083-31091.
134. Robinson, N.E. & A.B. Robinson 2001. Molecular clocks. Proc. Natl. Acad. Sci. USA 98: 944-949.
135. Deverman, B.E., B.L. Cook, S.R. Manson, et al. 2002. Bcl-xL deamidation is a critical switch in the regulation of the response to DNA damage. Cell 111: 51-62.
136. Zhao, R., D. Oxley, T.S. Smith, et al. 2007. DNA damage-induced Bcl-xL deamidation is mediated by NHE-1 antiport regulated intracellular pH. PLoS Biol. 5: e1.
137. Zhao, R., F.T. Yang, D.R. Alexander 2004. An oncogenic tyrosine kinase inhibits DNA repair and DNA-damage-induced Bcl-xL deamidation in T cell transformation. Cancer Cell 5: 37-49.
138. Zhao, R., G.A. Follows, P.A. Beer, et al. 2008. Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders. N. Engl. J. Med. 359: 2778-2789.
139. Shimada, K., T.R. Crother, J. Karlin, et al. 2012. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36: 401-414.
140. Faustin, B., Y. Chen, D. Zhai, et al. 2009. Mechanism of Bcl-2 and Bcl-X(L) inhibition of NLRP1 inflammasome: loop domain-dependent suppression of ATP binding and oligomerization. Proc. Natl. Acad. Sci. U.S.A. 106: 3935-3940.
141. Yeretssian, G., R.G. Correa, K. Doiron, et al. 2011. Non-apoptotic role of BID in inflammation and innate immunity. Nature 474: 96-99.
142. Guo, J.Y., Chen H-Y, R. Mathew, et al. 2011. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes. Dev. 25: 460-470.
143. Mathew, R. & E. White 2011. Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night. Curr. Opin. Genet. Dev. 21: 113-119.
144. Kuballa, P., W.M. Nolte, A.B. Castoreno & R.J. Xavier 2012. Autophagy and the immune system. Annu. Rev. Immunol. 30: 611-646.
145. Liang, X.H., L.K. Kleeman, H.H. Jiang, et al. 1998. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J. Virol. 72: 8586-8596.
146. Pattingre, S., A. Tassa, X. Qu, et al. 2005. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122: 927-939.
147. Maiuri, M.C., G. Le Toumelin, A. Criollo, et al. 2007. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J. 26: 2527-2539.
148. Maiuri, M.C., A. Criollo, E. Tasdemir, et al. 2007. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy 3: 374-376.
149. Priault, M., E. Hue, F. Marhuenda, et al. 2010. Differential dependence on Beclin 1 for the regulation of pro-survival autophagy by Bcl-2 and Bcl-xL in HCT116 colorectal cancer cells. PLoS One 5: e8755.
150. Okamoto, K. & J.M. Shaw 2005. Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu. Rev. Genet. 39: 503-536.
151. Martinou, J-C. & R.J. Youle 2011. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev. Cell 21: 92-101.
152. Karbowski, M., K.L. Norris, M.M. Cleland, et al. 2006. Role of Bax and Bak in mitochondrial morphogenesis. Nature 443: 658-662.
153. Cleland, M.M., K.L. Norris, M. Karbowski, et al. 2011. Bcl-2 family interaction with the mitochondrial morphogenesis machinery. Cell Death Differ. 18: 235-247.
154. Hoppins, S., F. Edlich, M.M. Cleland, et al. 2011. The soluble form of Bax regulates mitochondrial fusion via MFN2 homotypic complexes. Mol. Cell 41: 150-160.
155. Delivani, P., C. Adrain, R.C. Taylor, et al. 2006. Role for CED-9 and Egl-1 as regulators of mitochondrial fission and fusion dynamics. Molecular Cell 21: 761-773.
156. Campello, S., R.A. Lacalle, M. Bettella, et al. 2006. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J. Exp. Med. 203: 2879-2886.
157. Baixauli, F., N.B. Martín-Cófreces, G. Morlino, et al. 2011. The mitochondrial fission factor dynamin-related protein 1 modulates T-cell receptor signalling at the immune synapse. EMBO J. 30: 1238-1250.
158. Wang, R., C.P. Dillon, L.Z. Shi, et al. 2011. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35: 871-882.
159. Caro, P., A.U. Kishan, E. Norberg, et al. 2012. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 22: 547-560.
160. Perciavalle, R.M., D.P. Stewart, B. Koss, et al. 2012. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat. Cell Biol. 14: 575-583.
161. Chen, Z.X. & S. Pervaiz 2010. Involvement of cytochrome c oxidase subunits Va and Vb in the regulation of cancer cell metabolism by Bcl-2. Cell Death Differ. 17: 408-420.
162. Hockenbery, D.M., Z.N. Oltvai, X-M. Yin, et al. 1993. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75: 241-251.
163. Imahashi, K., M.D. Schneider, C. Steenbergen & E. Murphy 2004. Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ. Res. 95: 734-741.
164. Danial, N.N., L.D. Walensky, C-Y. Zhang, et al. 2008. Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat. Med. 14: 144-153.
165. Guicciardi, M.E. & G.J. Gores 2009. Life and death by death receptors. FASEB J. 23: 1625-1637.
166. The UniProt Consortium. 2011. Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res. 40: D71-D75.
167. Petros, A.M., D.G. Nettesheim, Y. Wang, et al. 2000. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci. 9: 2528-2534.
168. Hinds, M.G., C. Smits, R. Fredericks-Short, et al. 2007. Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets. Cell Death Differ. 14: 128-136.
169. Billen, L.P., A. Shamas-Din & D.W. Andrews 2009. Bid: a Bax-like BH3 protein. Oncogene 27: S93-S104.
170. Yan, N. & Y. Shi 2005. Mechanisms of apoptosis through structural biology. Ann. Rev. Cell Dev. Biol. 21: 35-56.
171. Wang, K., X.M. Yin, D.T. Chao, et al. 1996. BID: a novel BH3 domain-only death agonist. Genes. Dev. 10: 2859-2869.
172. Eskes, R., S. Desagher, B. Antonsson & J.C. Martinou 2000. Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol. Cell. Biol. 20: 929-935.
173. Cartron, P-F., T. Gallenne, G. Bougras, et al. 2004. The first [alpha] helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins Bid and PUMA. Mol. Cell 16: 807-818.
174. Kim, H., H-C. Tu, D. Ren, et al. 2009. Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol. Cell 36: 487-499.
175. Jabbour, A.M., J.E. Heraud, C.P. Daunt, et al. 2009. Puma indirectly activates Bax to cause apoptosis in the absence of Bid or Bim. Cell Death Differ. 16: 555-563.