title: Multiple functions of BCL-2 family proteins.
abstract: BCL-2 family proteins are the regulators of apoptosis, but also have other functions. This family of interacting partners includes inhibitors and inducers of cell death. Together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. This pathway is required for normal embryonic development and for preventing cancer. However, before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells. The relative importance of these physiological functions compared to their apoptosis functions in overall organismal physiology is difficult to decipher. Apoptotic and noncanonical functions of these proteins may be intertwined to link cell growth to cell death. Disentanglement of these functions may require delineation of biochemical activities inherent to the characteristic three-dimensional shape shared by distantly related viral and cellular BCL-2 family members.
authors: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA. hardwick@jhu.edu
authors: J Marie
authors: JM
authors: Hardwick
authors: Lucian
authors: L
authors: Soane
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D001343:Autophagy; D002118:Calcium / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000648:ultrastructure; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000502:physiology*; D014764:Viral Proteins / Q000737:chemistry / Q000502:physiology
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins; D002118:Calcium
references: Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):554-9
references: 9435230
references: Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7742-6
references: 1457005
references: Curr Opin Cell Biol. 2010 Apr;22(2):140-9
references: 20097051
references: EMBO J. 2004 Mar 10;23(5):1207-16
references: 15010700
references: Dev Cell. 2008 Feb;14(2):193-204
references: 18267088
references: Nature. 2005 Jun 2;435(7042):677-81
references: 15902208
references: Adv Exp Med Biol. 2010;687:1-32
references: 20919635
references: Dev Cell. 2011 May 17;20(5):663-76
references: 21571223
references: Biochim Biophys Acta. 2011 Apr;1813(4):597-607
references: 20950655
references: Autophagy. 2011 Aug;7(8):914-6
references: 21508685
references: Science. 2010 Dec 3;330(6009):1390-3
references: 21127253
references: J Cell Biol. 2002 Dec 23;159(6):931-8
references: 12499352
references: Methods Mol Biol. 2007;372:461-6
references: 18314745
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14345-50
references: 14610284
references: Genes Dev. 2007 Apr 15;21(8):929-41
references: 17403773
references: J Virol. 2007 Oct;81(20):11032-45
references: 17686864
references: EMBO J. 2010 Feb 3;29(3):606-18
references: 20010695
references: Dev Cell. 2001 Oct;1(4):515-25
references: 11703942
references: Genesis. 2007 Jun;45(6):396-404
references: 17506088
references: J Virol. 2009 Jul;83(14):7085-98
references: 19439472
references: Autophagy. 2007 Nov-Dec;3(6):561-8
references: 17643073
references: Development. 2011 Jan;138(2):327-38
references: 21177345
references: Cell Death Differ. 2009 Aug;16(8):1135-45
references: 19300452
references: Nat Med. 1999 Jul;5(7):832-5
references: 10395331
references: Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):6961-5
references: 1871110
references: Cell Cycle. 2011 Mar 15;10(6):989-98
references: 21368576
references: J Virol. 1997 May;71(5):4118-22
references: 9094693
references: EMBO J. 2008 Jan 23;27(2):433-46
references: 18200046
references: Cell. 1999 Mar 5;96(5):615-24
references: 10089877
references: Apoptosis. 2010 Mar;15(3):279-92
references: 20069458
references: Neuron. 1996 Sep;17(3):401-11
references: 8816704
references: J Biol Chem. 2004 Dec 24;279(52):54581-9
references: 15485871
references: Symp Soc Exp Biol. 2000;52:241-51
references: 12090012
references: Cell Death Differ. 2008 Jul;15(7):1139-46
references: 18451868
references: Dev Cell. 2003 Apr;4(4):575-85
references: 12689595
references: Cell. 2008 Dec 12;135(6):1074-84
references: 19062087
references: Cell. 1998 Aug 7;94(3):325-37
references: 9708735
references: PLoS One. 2010 Dec 20;5(12):e15636
references: 21203533
references: Autophagy. 2007 Mar-Apr;3(2):142-4
references: 17204849
references: Mol Cell. 2010 Dec 10;40(5):823-33
references: 21145489
references: Mol Cell. 2000 Jul;6(1):31-40
references: 10949025
references: Autophagy. 2008 Nov;4(8):989-97
references: 18797192
references: Protein Sci. 2007 Jan;16(1):118-24
references: 17123957
references: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2169-74
references: 18250306
references: Cell. 2000 Dec 8;103(6):839-42
references: 11136969
references: EMBO J. 2011 Apr 6;30(7):1195-208
references: 21358617
references: Nature. 1992 Apr 9;356(6369):494-9
references: 1560823
references: J Neurosci. 2004 Dec 8;24(49):11205-13
references: 15590937
references: Cell. 1993 Nov 19;75(4):641-52
references: 8242740
references: PLoS Biol. 2008 Jun 17;6(6):e154
references: 18563968
references: Nat Med. 2008 Feb;14(2):144-53
references: 18223655
references: Cell. 1998 Aug 21;94(4):481-90
references: 9727491
references: Nat Med. 2000 Nov;6(11):1241-7
references: 11062535
references: J Neurosci. 2003 Sep 10;23(23):8423-31
references: 12968005
references: Mol Cell Biol. 1997 Dec;17(12):7040-6
references: 9372935
references: Science. 1997 Dec 12;278(5345):1966-8
references: 9395403
references: Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17404-9
references: 15585581
references: Cell Death Differ. 2000 Jul;7(7):666-74
references: 10889511
references: Genes Dev. 2002 Oct 1;16(19):2465-78
references: 12368257
references: Protein Sci. 2000 Dec;9(12):2528-34
references: 11206074
references: PLoS Pathog. 2008 Aug 15;4(8):e1000128
references: 18704168
references: Cell. 2012 Jun 22;149(7):1536-48
references: 22726440
references: Mol Cell Biol. 2006 Oct;26(20):7397-408
references: 17015472
references: J Biol Chem. 2006 Dec 22;281(51):39728-39
references: 17074758
references: Cell Death Differ. 2008 Oct;15(10):1564-71
references: 18551131
references: J Neurophysiol. 2008 Mar;99(3):1515-22
references: 18160428
references: J Virol. 2000 Jun;74(11):5024-31
references: 10799576
references: Cell. 2010 Sep 17;142(6):889-901
references: 20850011
references: PLoS Pathog. 2008 Feb 8;4(2):e25
references: 18248095
references: Science. 1985 Jun 21;228(4706):1440-3
references: 3874430
references: Acta Neuropathol. 2006 Feb;111(2):93-100
references: 16468021
references: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):105-10
references: 15613488
references: Mol Cell Biol. 2001 May;21(9):3025-36
references: 11287608
references: Nature. 1997 Jan 23;385(6614):353-7
references: 9002522
references: J Biol Chem. 2005 Jun 24;280(25):23829-36
references: 15809295
references: EMBO J. 2007 May 16;26(10):2527-39
references: 17446862
references: J Cell Sci. 2008 Oct 15;121(Pt 20):3373-82
references: 18827010
references: Cell Death Differ. 2008 Jul;15(7):1147-52
references: 18437161
references: Immunity. 2007 Aug;27(2):268-80
references: 17692540
references: Cell. 1997 Oct 17;91(2):231-41
references: 9346240
references: Nature. 1996 Feb 8;379(6565):554-6
references: 8596636
references: Nature. 1994 May 26;369(6478):318-20
references: 7910376
references: Nature. 1988 Sep 29;335(6189):440-2
references: 3262202
references: Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6566-71
references: 22493254
references: J Virol. 2002 Mar;76(5):2469-79
references: 11836425
references: Mol Cell. 2008 Jul 25;31(2):255-65
references: 18657507
references: Nature. 2005 Feb 17;433(7027):754-60
references: 15716954
references: J Gen Virol. 2007 Jun;88(Pt 6):1656-1666
references: 17485524
references: PLoS Pathog. 2010 Aug 19;6(8):e1001063
references: 20808852
references: J Virol. 2007 Jul;81(13):7178-88
references: 17475653
references: Nat Rev Neurosci. 2008 Jul;9(7):505-18
references: 18568013
references: Nature. 1998 Jan 29;391(6666):496-9
references: 9461218
references: J Neurosci. 2004 Jan 21;24(3):743-51
references: 14736860
references: J Clin Oncol. 2011 Mar 1;29(7):909-16
references: 21282543
references: J Biol Chem. 1999 Jan 8;274(2):1156-63
references: 9873064
references: Cell. 1994 Feb 25;76(4):665-76
references: 7907274
references: Mol Cell. 2011 Jan 21;41(2):150-60
references: 21255726
references: Cancer Res. 2008 May 1;68(9):3421-8
references: 18451170
references: Cancer Cell. 2007 Aug;12(2):171-85
references: 17692808
references: Cell Cycle. 2011 May 1;10(9):1350-51
references: 21487234
references: J Biol Chem. 2007 Apr 27;282(17):13123-32
references: 17337444
references: Cell Death Differ. 2011 Apr;18(4):571-80
references: 21311563
references: Nature. 2003 Aug 21;424(6951):952-6
references: 12931191
references: Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1092-100
references: 16115013
references: Development. 2009 Jan;136(2):275-83
references: 19088092
references: Apoptosis. 2008 Aug;13(8):1022-30
references: 18584327
references: Neuron. 2011 May 26;70(4):758-72
references: 21609830
references: Mol Cell. 2009 Feb 13;33(3):377-88
references: 19217411
references: Nat Rev Mol Cell Biol. 2007 Nov;8(11):870-9
references: 17928812
references: PLoS Biol. 2005 Dec;3(12):e404
references: 16277553
references: Mol Cell. 2000 Jul;6(1):53-63
references: 10949027
references: Apoptosis. 2009 Jul;14(7):923-5
references: 19543976
references: Mol Cell. 2000 Dec;6(6):1389-99
references: 11163212
references: Biochim Biophys Acta. 2011 Apr;1813(4):540-5
references: 21277336
references: Cell. 1998 Sep 18;94(6):739-50
references: 9753321
references: Curr Opin Cell Biol. 2003 Dec;15(6):700-5
references: 14644194
references: J Biol Chem. 2009 Apr 10;284(15):9692-9
references: 19228691
references: Blood. 2010 Apr 22;115(16):3304-13
references: 20197552
references: Cell. 2005 Sep 23;122(6):927-39
references: 16179260
references: Genes Dev. 1996 Nov 15;10(22):2859-69
references: 8918887
references: Autophagy. 2011 May;7(5):549-51
references: 21412051
references: Cell. 2002 Nov 1;111(3):331-42
references: 12419244
references: Cell Death Differ. 2006 Aug;13(8):1409-18
references: 16729032
references: Cell Death Differ. 2003 Feb;10(2):260-1
references: 12700655
references: Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8479-83
references: 8397406
references: Nat Rev Immunol. 2005 Mar;5(3):189-200
references: 15719025
references: Science. 2003 Jul 25;301(5632):513-7
references: 12881569
references: Cell. 2005 Aug 26;122(4):579-91
references: 16122425
references: EMBO J. 1999 Feb 1;18(3):632-43
references: 9927423
references: J Biol Chem. 2011 Jul 15;286(28):25098-107
references: 21613222
references: Nature. 1996 Nov 28;384(6607):368-72
references: 8934524
references: PLoS Pathog. 2009 Oct;5(10):e1000609
references: 19816569
references: Cell. 1993 Aug 27;74(4):609-19
references: 8358790
references: Mol Brain. 2012 May 14;5:15
references: 22583788
references: J Biol Chem. 2010 Apr 30;285(18):13678-84
references: 20189983
references: Curr Biol. 1997 Dec 1;7(12):913-20
references: 9382837
references: Cold Spring Harb Symp Quant Biol. 1983;48 Pt 2:453-63
references: 6586368
references: Curr Mol Med. 2006 Feb;6(1):99-109
references: 16472117
references: Acta Virol. 2007;51(2):101-8
references: 17900216
references: J Exp Med. 2005 Mar 21;201(6):1007-18
references: 15767367
references: J Biol Chem. 2001 Jun 1;276(22):19414-9
references: 11259441
references: J Mol Biol. 2009 Jan 23;385(3):843-53
references: 18845156
references: Cancer Res. 1997 Aug 1;57(15):3115-20
references: 9242435
references: Science. 2001 Sep 7;293(5536):1829-32
references: 11546872
references: Nat Cell Biol. 2005 Oct;7(10):1021-8
references: 16179951
references: Semin Cancer Biol. 1993 Dec;4(6):327-32
references: 8142617
references: Physiol Rev. 1968 Jul;48(3):534-69
references: 4875350
references: Cancer Cell. 2002 Mar;1(2):169-79
references: 12086875
references: Nature. 2011 Jan 20;469(7330):323-35
references: 21248839
references: Science. 1984 Nov 30;226(4678):1097-9
references: 6093263
references: Br J Cancer. 1972 Aug;26(4):239-57
references: 4561027
references: Ann N Y Acad Sci. 2000;917:541-8
references: 11268382
references: Science. 2010 May 21;328(5981):1025-9
references: 20395473
references: J Virol. 2006 Feb;80(3):1140-51
references: 16414991
references: Science. 2003 Apr 4;300(5616):135-9
references: 12624178
references: Biochim Biophys Acta. 2004 Dec 6;1659(2-3):178-89
references: 15576050
references: Biochim Biophys Acta. 2011 Apr;1813(4):508-20
references: 21146563
references: Neuron. 2012 May 24;74(4):719-30
references: 22632729
references: Nature. 1996 May 23;381(6580):335-41
references: 8692274
references: Trends Neurosci. 2005 Jun;28(6):284-9
references: 15927683
references: FEBS Lett. 2010 Aug 4;584(15):3323-30
references: 20627101
references: J Cell Biol. 2011 Oct 17;195(2):263-76
references: 21987637
references: Dev Cell. 2002 Jan;2(1):55-67
references: 11782314
references: Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4904-9
references: 22416118
references: Nature. 2011 Jun 2;474(7349):96-9
references: 21552281
references: J Biol Chem. 2005 Feb 11;280(6):4491-7
references: 15561723
references: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4997-5002
references: 9560217
references: Nat Cell Biol. 2012 Apr 29;14(6):575-83
references: 22544066
references: Nature. 2006 Oct 12;443(7112):658-62
references: 17035996
references: J Biol Chem. 2004 Oct 1;279(40):42240-9
references: 15231831
references: J Biol Chem. 1993 Mar 25;268(9):6511-9
references: 8454620
references: Oncogene. 2013 May 2;32(18):2304-14
references: 22710714
references: Science. 2004 Feb 13;303(5660):1010-4
references: 14963330
references: Mol Cell Biol. 2011 Nov;31(21):4298-309
references: 21859891
references: Nature. 2011 Mar 17;471(7338):310-2
references: 21412328
references: Trends Cell Biol. 2012 Jun;22(6):318-28
references: 22560661
references: Cell Death Differ. 2005 Oct;12(10):1310-8
references: 15905879
references: Trends Cell Biol. 2002 Apr;12(4):178-84
references: 11978537
references: Mol Cell. 2006 Mar 17;21(6):761-73
references: 16543146
references: J Cell Biol. 2009 Aug 24;186(4):525-40
references: 19704021
references: Protein Sci. 2007 Apr;16(4):695-703
references: 17384234
references: Biochim Biophys Acta. 2009 Jun;1793(6):971-8
references: 19056433
references: Mol Cell. 1999 Nov;4(5):815-26
references: 10619028
references: PLoS Biol. 2008 Jun 10;6(6):e147
references: 18547146
references: Proc Natl Acad Sci U S A. 1989 Jun;86(12):4589-93
references: 2543982
references: Autophagy. 2007 Jul-Aug;3(4):374-6
references: 17438366
references: Nat Neurosci. 2012 Feb 26;15(4):574-80
references: 22366758
references: Mol Cell. 2001 Sep;8(3):705-11
references: 11583631
references: Cell. 1999 Mar 5;96(5):625-34
references: 10089878
references: J Cell Biol. 1999 Nov 15;147(4):809-22
references: 10562282
references: Proc Natl Acad Sci U S A. 1989 Mar;86(6):1958-62
references: 2538824
references: Cell. 1998 Aug 21;94(4):491-501
references: 9727492
references: Cell Death Differ. 2007 Jan;14(1):128-36
references: 16645638
references: Curr Biol. 2009 May 12;19(9):768-73
references: 19327994
references: Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):690-4
references: 9012846
references: Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13590-5
references: 15342906
references: Nature. 2011 Apr 28;472(7344):466-70
references: 21460835
references: Nat Cell Biol. 2011 Sep 18;13(10):1224-33
references: 21926988
references: J Cell Biol. 2009 Mar 9;184(5):707-19
references: 19255249
references: Oncogene. 2006 Aug 7;25(34):4697-705
references: 16892083
references: Virol J. 2010 Mar 15;7:59
references: 20230632
references: Autophagy. 2008 Jul;4(5):600-6
references: 18497563
references: Mol Cell Biol. 2002 Mar;22(5):1369-78
references: 11839804
references: Biochem J. 2004 Oct 15;383(Pt 2):361-70
references: 15245329
references: Curr Biol. 2008 Jul 8;18(13):933-42
references: 18571408
references: Dev Biol. 1990 Mar;138(1):33-41
references: 2307287