Induction of the apoptosis inhibitor ARC by Ras in human cancers.
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.
Wu
Lily
L
Department of Medicine, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Nam
Young-Jae
YJ
Kung
Gloria
G
Crow
Michael T
MT
Kitsis
Richard N
RN
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*
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
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