Regulation of mitochondrial apoptotic events by p53-mediated disruption of complexes between antiapoptotic Bcl-2 members and Bim.
Multiple mechanisms have been proposed for the mitochondrial function of p53 that are either dependent on or independent of its transcriptional activity. However, none of these mechanisms involves Bim functioning downstream of p53 mitochondrial translocation. Utilizing a p53 nuclear localization signal mutant, whose nuclear import is completely abrogated, we demonstrate that its apoptotic activity at the outer mitochondrial membrane, which involves conformational changes in Bax and Bak, is mediated by Bim. We further demonstrate an inverse correlation between the binding levels of p53 and Bim to Mcl-1. Thus, enhanced binding of p53 to Mcl-1 involves the disruption of existing complexes between Mcl-1 and Bim. We propose that mitochondrial p53 functions as a Bim derepressor by releasing Bim from sequestrating complexes with Mcl-1, Bcl-2, and Bcl-XL, and allowing its engagement in Bak/Bax activation.
Han
Jie
J
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Goldstein
Leslie A
LA
Hou
Wen
W
Gastman
Brian R
BR
Rabinowich
Hannah
H
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D006801:Humans; D047468:Immunoprecipitation; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019913:Nuclear Localization Signals / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013312:Stress, Physiological; D013347:Subcellular Fractions / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019913:Nuclear Localization Signals; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein
Mol Cell. 2005 Feb 4;17(3):393-403
15694340
Cancer Cell. 2008 Oct 7;14(4):285-98
18835031
J Biol Chem. 1998 Apr 24;273(17):10777-83
9553144
Mol Cell. 2003 Mar;11(3):577-90
12667443
FEBS Lett. 2004 Feb 13;559(1-3):171-4
14960327
Blood. 2005 Dec 15;106(13):4131-8
16118324
Oncogene. 2001 Nov 15;20(52):7668-76
11753644
Cancer Cell. 2006 May;9(5):351-65
16697956
Nature. 2009 Apr 30;458(7242):1127-30
19407794
J Biol Chem. 2007 Jun 1;282(22):16223-31
17374615
J Exp Med. 2001 Nov 5;194(9):1325-37
11696597
Cancer Res. 2005 Nov 1;65(21):9971-81
16267022
Oncogene. 1993 Jan;8(1):203-7
8093810
Nature. 2003 Dec 11;426(6967):671-6
14668867
Nat Cell Biol. 2004 May;6(5):443-50
15077116
J Biol Chem. 2006 Mar 31;281(13):8600-6
16443602
Cell Cycle. 2009 Jun 1;8(11):1711-9
19411846
Mol Cell. 2001 Mar;7(3):673-82
11463391
Science. 2001 Apr 27;292(5517):727-30
11326099
Cancer Cell. 2002 Sep;2(3):183-92
12242151
J Cell Biol. 1999 Mar 8;144(5):903-14
10085290
Cell Res. 2008 Jul;18(7):733-44
18504456
Proc Natl Acad Sci U S A. 2004 May 18;101(20):7681-6
15136728
Nature. 2008 Oct 23;455(7216):1076-81
18948948
Gene. 1989 Apr 15;77(1):51-9
2744487
Science. 2007 Feb 9;315(5813):856-9
17289999
Science. 2000 May 12;288(5468):1053-8
10807576
Cancer Cell. 2007 Aug;12(2):171-85
17692808
Cancer Cell. 2007 Jul;12(1):66-80
17613437
Cancer Cell. 2002 Apr;1(3):289-98
12086865
Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59
18097445
Cell Death Differ. 2006 Jun;13(6):994-1002
16543937
Science. 2005 Sep 9;309(5741):1732-5
16151013
Mol Cell. 2001 Mar;7(3):683-94
11463392
J Clin Invest. 1999 Aug;104(3):263-9
10430607
Biochem Biophys Res Commun. 2005 Jun 10;331(3):843-50
15865940
Science. 2003 Nov 7;302(5647):1036-8
14500851
J Cell Biol. 2009 Aug 10;186(3):355-62
19651893
Mol Cell. 2005 Feb 18;17(4):525-35
15721256
J Clin Immunol. 2003 Sep;23(5):355-61
14601643
Curr Opin Cell Biol. 2005 Dec;17(6):631-6
16226451
J Exp Med. 2006 May 15;203(5):1147-52
16651384
Mol Cell Biol. 2003 Sep;23(18):6396-405
12944468
Science. 2004 Feb 13;303(5660):1010-4
14963330
J Biol Chem. 2004 May 21;279(21):22020-9
15014070
J Biol Chem. 2005 Apr 22;280(16):16383-92
15713684
J Biol Chem. 2006 Apr 14;281(15):10153-63
16478725
Mol Cell. 2001 Sep;8(3):705-11
11583631
Biochim Biophys Acta. 2009 May;1787(5):414-20
19007744
Nat Rev Cancer. 2002 Aug;2(8):594-604
12154352
EMBO J. 1998 Jan 15;17(2):384-95
9430630
Oncogene. 1994 Jun;9(6):1799-805
8183579