title: Induction of the apoptosis inhibitor ARC by Ras in human cancers.
abstract: Inhibition of apoptosis is critical for carcinogenesis. ARC (apoptosis repressor with caspase recruitment domain) is an endogenous inhibitor of apoptosis that antagonizes both intrinsic and extrinsic apoptosis pathways. Although normally expressed in striated myocytes and neurons, ARC is markedly induced in a variety of primary human epithelial cancers and renders cancer cells resistant to killing. The mechanisms that mediate the induction of ARC in cancer are unknown. Herein we demonstrate that increases in ARC abundance are stimulated by Ras through effects on transcription and protein stability. Overexpression of activated N-Ras or H-Ras in normal cells is sufficient to increase ARC mRNA and protein levels. Similarly, transgenic expression of activated H-Ras induces ARC in both the normal mammary epithelium and resulting tumors of intact mice. Conversely, knockdown of endogenous N-Ras in breast and colon cancer cells significantly reduces ARC mRNA and protein levels. The promoter of the Nol3 locus, encoding ARC, is activated by N-Ras and H-Ras in a MEK/ERK-dependent manner. Ras also stabilizes ARC protein by suppressing its polyubiquitination and subsequent proteasomal degradation. In addition to the effects of Ras on ARC abundance, ARC mediates Ras-induced cell survival and cell cycle progression. Thus, Ras induces ARC in epithelial cancers, and ARC plays a role in the oncogenic actions of Ras.
authors.affiliation: Department of Medicine, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Wu
authors.forename: Young-Jae
authors.initials: YJ
authors.lastname: Nam
authors.forename: Gloria
authors.initials: G
authors.lastname: Kung
authors.forename: Michael T
authors.initials: MT
authors.lastname: Crow
authors.forename: Richard N
authors.initials: RN
authors.lastname: Kitsis
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D061988:Proteasome Inhibitors; D051381:Rats; D012878:Skin Neoplasms / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D061988:Proteasome Inhibitors; C092069:activity regulated cytoskeletal-associated protein; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D020169:Caspases; D018631:ras Proteins
references.citation: J Cell Biochem. 2007 Oct 15;102(3):549-59
references.pmid: 17661355
references.citation: Mol Cell. 2003 Dec;12(6):1413-26
references.pmid: 14690596
references.citation: J Cell Biol. 1994 Feb;124(4):619-26
references.pmid: 8106557
references.citation: Cell Cycle. 2008 Jun 1;7(11):1640-7
references.pmid: 18469522
references.citation: Cancer Res. 1990 Oct 15;50(20):6701-7
references.pmid: 2208136
references.citation: J Biol Chem. 2004 May 14;279(20):21233-8
references.pmid: 15004034
references.citation: Cell. 2004 Jan 23;116(2):205-19
references.pmid: 14744432
references.citation: Biochim Biophys Acta. 1996 May 2;1306(2-3):147-52
references.pmid: 8634331
references.citation: Cancer Res. 1985 May;45(5):2201-5
references.pmid: 3986769
references.citation: Oncogene. 2003 Dec 8;22(56):8999-9006
references.pmid: 14663478
references.citation: Nat Rev Mol Cell Biol. 2008 Mar;9(3):231-41
references.pmid: 18073771
references.citation: Curr Opin Genet Dev. 1994 Feb;4(1):120-9
references.pmid: 8193531
references.citation: Science. 1997 Feb 21;275(5303):1132-6
references.pmid: 9027315
references.citation: Cancer Res. 1995 Dec 1;55(23):5536-9
references.pmid: 7585629
references.citation: Cancer Sci. 2004 Aug;95(8):626-33
references.pmid: 15298723
references.citation: Cancer Res. 2004 Jul 1;64(13):4585-92
references.pmid: 15231670
references.citation: Nature. 1987 May 28-Jun 3;327(6120):293-7
references.pmid: 3587348
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1263-84
references.pmid: 17126425
references.citation: Nat Rev Cancer. 2006 Jun;6(6):449-58
references.pmid: 16723991
references.citation: EMBO J. 2002 Jul 15;21(14):3704-14
references.pmid: 12110583
references.citation: J Biol Chem. 2007 Feb 23;282(8):5522-8
references.pmid: 17142452
references.citation: J Biol Chem. 2006 Feb 17;281(7):3800-9
references.pmid: 16316983
references.citation: Methods. 2003 Jul;30(3):256-68
references.pmid: 12798140
references.citation: Oncogene. 2000 Feb 17;19(7):961-4
references.pmid: 10702805
references.citation: Breast Cancer Res Treat. 1995 Jul;35(1):133-44
references.pmid: 7612899
references.citation: Neuropathol Appl Neurobiol. 2002 Dec;28(6):480-8
references.pmid: 12445164
references.citation: Am J Pathol. 2006 Jan;168(1):292-309
references.pmid: 16400031
references.citation: J Biol Chem. 2007 Feb 23;282(8):5529-35
references.pmid: 17142834
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5156-60
references.pmid: 9560245
references.citation: Trends Biochem Sci. 1998 Jun;23(6):213-6
references.pmid: 9644975
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20826-31
references.pmid: 18087040
references.citation: J Biol Chem. 1999 Apr 16;274(16):10951-62
references.pmid: 10196175
references.citation: Mol Cell Biol. 2008 Jan;28(2):564-74
references.pmid: 17998337
references.citation: Cell Death Differ. 2005 Jun;12(6):682-6
references.pmid: 15861191
references.citation: Cell. 1987 May 22;49(4):465-75
references.pmid: 3032456
references.citation: Science. 2004 Apr 23;304(5670):554
references.pmid: 15016963
references.citation: Oncogene. 1989 Feb;4(2):145-51
references.pmid: 2564657
references.citation: Cancer Res. 2008 Feb 1;68(3):834-42
references.pmid: 18245485
references.citation: Nat Rev Cancer. 2008 Feb;8(2):121-32
references.pmid: 18202696
references.citation: Science. 1994 Aug 12;265(5174):966-70
references.pmid: 8052857
references.citation: Methods Cell Biol. 1994;41:389-400
references.pmid: 7861971
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: EMBO J. 1996 Dec 2;15(23):6541-51
references.pmid: 8978681
references.citation: Nucleic Acids Res. 1999 Jul 15;27(14):2947-56
references.pmid: 10390538
references.citation: Nat Rev Mol Cell Biol. 2004 May;5(5):355-66
references.pmid: 15122349
references.citation: Mol Cell. 2004 Sep 24;15(6):901-12
references.pmid: 15383280
references.citation: Nat Rev Mol Cell Biol. 2002 Jun;3(6):401-10
references.pmid: 12042762