title: Identification of a protein, G0S2, that lacks Bcl-2 homology domains and interacts with and antagonizes Bcl-2.
abstract: The Bcl-2 family of proteins consists of both antiapoptotic and proapoptotic factors, which share sequence homology within conserved regions known as Bcl-2 homology domains. Interactions between Bcl-2 family members, as well as with other proteins, regulate apoptosis through control of mitochondrial membrane permeability and release of cytochrome c. Here we identify a novel regulator of apoptosis that lacks Bcl-2 homology domains but acts by binding Bcl-2 and modulating its antiapoptotic activity. To identify regulators of apoptosis, we performed expression profiling in human primary fibroblasts treated with tumor necrosis factor-alpha (TNF-alpha), a potent inflammatory cytokine that can regulate apoptosis and functions, at least in part, by inducing expression of specific genes through NF-kappaB. We found that the gene undergoing maximal transcriptional induction following TNF-alpha treatment was G(0)-G(1) switch gene 2 (G0S2), the activation of which also required NF-kappaB. We show that G0S2 encodes a mitochondrial protein that specifically interacts with Bcl-2 and promotes apoptosis by preventing the formation of protective Bcl-2/Bax heterodimers. We further show that ectopic expression of G0S2 induces apoptosis in diverse human cancer cell lines in which endogenous G0S2 is normally epigenetically silenced. Our results reveal a novel proapoptotic factor that is induced by TNF-alpha through NF-kappaB and that interacts with and antagonizes Bcl-2.
authors.affiliation: Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Welch
authors.forename: Manas K
authors.initials: MK
authors.lastname: Santra
authors.forename: Wissal
authors.initials: W
authors.lastname: El-Assaad
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Zhu
authors.forename: Wade E
authors.initials: WE
authors.lastname: Huber
authors.forename: Richard A
authors.initials: RA
authors.lastname: Keys
authors.forename: Jose G
authors.initials: JG
authors.lastname: Teodoro
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C508073:G0S2 protein, human; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein
references.citation: Eur Rev Med Pharmacol Sci. 2009 Jan-Feb;13(1):23-40
references.pmid: 19364083
references.citation: Science. 1996 Nov 1;274(5288):782-4
references.pmid: 8864118
references.citation: Int J Oncol. 1993 Nov;3(5):781-8
references.pmid: 21573432
references.citation: Oncogene. 2007 Feb 26;26(9):1324-37
references.pmid: 17322918
references.citation: Mol Cell Biol. 2000 Apr;20(8):2687-95
references.pmid: 10733571
references.citation: J Biol Chem. 2001 Dec 28;276(52):48921-9
references.pmid: 11679590
references.citation: J Biol Chem. 1997 Dec 5;272(49):31065-72
references.pmid: 9388257
references.citation: Nat Rev Cancer. 2008 Feb;8(2):121-32
references.pmid: 18202696
references.citation: J Biol Chem. 1997 May 23;272(21):13829-34
references.pmid: 9153240
references.citation: Oncogene. 2003 Apr 3;22(13):2054-64
references.pmid: 12673210
references.citation: Cell. 2007 Apr 6;129(1):45-56
references.pmid: 17418785
references.citation: Neoplasia. 2004 Jan-Feb;6(1):1-6
references.pmid: 15068665
references.citation: Nat Rev Genet. 2005 Aug;6(8):597-610
references.pmid: 16136652
references.citation: J Biol Chem. 1998 Mar 13;273(11):6110-20
references.pmid: 9497329
references.citation: Apoptosis. 1999 Aug;4(4):291-301
references.pmid: 14692400
references.citation: J Biol Chem. 1990 Feb 15;265(5):2973-8
references.pmid: 2406243
references.citation: Nat Genet. 1999 Jan;21(1):103-7
references.pmid: 9916800
references.citation: Nat Med. 1999 Apr;5(4):412-7
references.pmid: 10202930
references.citation: Cell. 1989 Dec 22;59(6):1203-11
references.pmid: 2688898
references.citation: Clin Cancer Res. 2007 Dec 15;13(24):7254-63
references.pmid: 18094405
references.citation: Cell. 1993 Aug 27;74(4):609-19
references.pmid: 8358790
references.citation: Oncogene. 2006 Oct 30;25(51):6800-16
references.pmid: 17072329
references.citation: Biochem Pharmacol. 2004 Jan 15;67(2):353-64
references.pmid: 14698047
references.citation: Cell. 1997 Oct 17;91(2):243-52
references.pmid: 9346241
references.citation: Science. 1996 Nov 1;274(5288):787-9
references.pmid: 8864120
references.citation: J Exp Med. 1998 Jul 6;188(1):211-6
references.pmid: 9653098
references.citation: Front Biosci. 2008 Jan 01;13:2736-43
references.pmid: 17981749
references.citation: Cancer Res. 2004 Sep 1;64(17):5982-7
references.pmid: 15342377
references.citation: DNA Cell Biol. 1991 Oct;10(8):581-91
references.pmid: 1930693
references.citation: J Immunol. 2003 Apr 15;170(8):4053-60
references.pmid: 12682234
references.citation: Mol Cell Biol. 2002 Jul;22(13):4929-42
references.pmid: 12052897