title: Regulation of mitochondrial apoptotic events by p53-mediated disruption of complexes between antiapoptotic Bcl-2 members and Bim.
abstract: 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.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Han
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Goldstein
authors.forename: Wen
authors.initials: W
authors.lastname: Hou
authors.forename: Brian R
authors.initials: BR
authors.lastname: Gastman
authors.forename: Hannah
authors.initials: H
authors.lastname: Rabinowich
mesh_terms: 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
chemical_list: 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
references.citation: Mol Cell. 2005 Feb 4;17(3):393-403
references.pmid: 15694340
references.citation: Cancer Cell. 2008 Oct 7;14(4):285-98
references.pmid: 18835031
references.citation: J Biol Chem. 1998 Apr 24;273(17):10777-83
references.pmid: 9553144
references.citation: Mol Cell. 2003 Mar;11(3):577-90
references.pmid: 12667443
references.citation: FEBS Lett. 2004 Feb 13;559(1-3):171-4
references.pmid: 14960327
references.citation: Blood. 2005 Dec 15;106(13):4131-8
references.pmid: 16118324
references.citation: Oncogene. 2001 Nov 15;20(52):7668-76
references.pmid: 11753644
references.citation: Cancer Cell. 2006 May;9(5):351-65
references.pmid: 16697956
references.citation: Nature. 2009 Apr 30;458(7242):1127-30
references.pmid: 19407794
references.citation: J Biol Chem. 2007 Jun 1;282(22):16223-31
references.pmid: 17374615
references.citation: J Exp Med. 2001 Nov 5;194(9):1325-37
references.pmid: 11696597
references.citation: Cancer Res. 2005 Nov 1;65(21):9971-81
references.pmid: 16267022
references.citation: Oncogene. 1993 Jan;8(1):203-7
references.pmid: 8093810
references.citation: Nature. 2003 Dec 11;426(6967):671-6
references.pmid: 14668867
references.citation: Nat Cell Biol. 2004 May;6(5):443-50
references.pmid: 15077116
references.citation: J Biol Chem. 2006 Mar 31;281(13):8600-6
references.pmid: 16443602
references.citation: Cell Cycle. 2009 Jun 1;8(11):1711-9
references.pmid: 19411846
references.citation: Mol Cell. 2001 Mar;7(3):673-82
references.pmid: 11463391
references.citation: Science. 2001 Apr 27;292(5517):727-30
references.pmid: 11326099
references.citation: Cancer Cell. 2002 Sep;2(3):183-92
references.pmid: 12242151
references.citation: J Cell Biol. 1999 Mar 8;144(5):903-14
references.pmid: 10085290
references.citation: Cell Res. 2008 Jul;18(7):733-44
references.pmid: 18504456
references.citation: Proc Natl Acad Sci U S A. 2004 May 18;101(20):7681-6
references.pmid: 15136728
references.citation: Nature. 2008 Oct 23;455(7216):1076-81
references.pmid: 18948948
references.citation: Gene. 1989 Apr 15;77(1):51-9
references.pmid: 2744487
references.citation: Science. 2007 Feb 9;315(5813):856-9
references.pmid: 17289999
references.citation: Science. 2000 May 12;288(5468):1053-8
references.pmid: 10807576
references.citation: Cancer Cell. 2007 Aug;12(2):171-85
references.pmid: 17692808
references.citation: Cancer Cell. 2007 Jul;12(1):66-80
references.pmid: 17613437
references.citation: Cancer Cell. 2002 Apr;1(3):289-98
references.pmid: 12086865
references.citation: Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59
references.pmid: 18097445
references.citation: Cell Death Differ. 2006 Jun;13(6):994-1002
references.pmid: 16543937
references.citation: Science. 2005 Sep 9;309(5741):1732-5
references.pmid: 16151013
references.citation: Mol Cell. 2001 Mar;7(3):683-94
references.pmid: 11463392
references.citation: J Clin Invest. 1999 Aug;104(3):263-9
references.pmid: 10430607
references.citation: Biochem Biophys Res Commun. 2005 Jun 10;331(3):843-50
references.pmid: 15865940
references.citation: Science. 2003 Nov 7;302(5647):1036-8
references.pmid: 14500851
references.citation: J Cell Biol. 2009 Aug 10;186(3):355-62
references.pmid: 19651893
references.citation: Mol Cell. 2005 Feb 18;17(4):525-35
references.pmid: 15721256
references.citation: J Clin Immunol. 2003 Sep;23(5):355-61
references.pmid: 14601643
references.citation: Curr Opin Cell Biol. 2005 Dec;17(6):631-6
references.pmid: 16226451
references.citation: J Exp Med. 2006 May 15;203(5):1147-52
references.pmid: 16651384
references.citation: Mol Cell Biol. 2003 Sep;23(18):6396-405
references.pmid: 12944468
references.citation: Science. 2004 Feb 13;303(5660):1010-4
references.pmid: 14963330
references.citation: J Biol Chem. 2004 May 21;279(21):22020-9
references.pmid: 15014070
references.citation: J Biol Chem. 2005 Apr 22;280(16):16383-92
references.pmid: 15713684
references.citation: J Biol Chem. 2006 Apr 14;281(15):10153-63
references.pmid: 16478725
references.citation: Mol Cell. 2001 Sep;8(3):705-11
references.pmid: 11583631
references.citation: Biochim Biophys Acta. 2009 May;1787(5):414-20
references.pmid: 19007744
references.citation: Nat Rev Cancer. 2002 Aug;2(8):594-604
references.pmid: 12154352
references.citation: EMBO J. 1998 Jan 15;17(2):384-95
references.pmid: 9430630
references.citation: Oncogene. 1994 Jun;9(6):1799-805
references.pmid: 8183579