Induction of the apoptosis inhibitor ARC by Ras in human cancers

Lily Wu, Young Jae Nam, Gloria Kung, Michael T. Crow, Richard N. Kitsis

Research output: Contribution to journalArticle

19 Scopus citations

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 ofARCin cancer are unknown. Herein we demonstrate that increases inARCabundance 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.

Original languageEnglish (US)
Pages (from-to)19235-19245
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number25
DOIs
StatePublished - Jun 18 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Induction of the apoptosis inhibitor ARC by Ras in human cancers'. Together they form a unique fingerprint.

  • Cite this