Targeting of C-terminal binding protein (CtBP) by ARF results in p53-independent apoptosis

Mol Cell Biol. 2006 Mar;26(6):2360-72. doi: 10.1128/MCB.26.6.2360-2372.2006.

Abstract

ARF encodes a potent tumor suppressor that antagonizes MDM2, a negative regulator of p53. ARF also suppresses the proliferation of cells lacking p53, and loss of ARF in p53-null mice, compared with ARF or p53 singly null mice, results in a broadened tumor spectrum and decreased tumor latency. To investigate the mechanism of p53-independent tumor suppression by ARF, potential interacting proteins were identified by yeast two-hybrid screen. The antiapoptotic transcriptional corepressor C-terminal binding protein 2 (CtBP2) was identified, and ARF interactions with both CtBP1 and CtBP2 were confirmed in vitro and in vivo. Interaction with ARF resulted in proteasome-dependent CtBP degradation. Both ARF-induced CtBP degradation and CtBP small interfering RNA led to p53-independent apoptosis in colon cancer cells. ARF induction of apoptosis was dependent on its ability to interact with CtBP, and reversal of ARF-induced CtBP depletion by CtBP overexpression abrogated ARF-induced apoptosis. CtBP proteins represent putative targets for p53-independent tumor suppression by ARF.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism*
  • Alcohol Oxidoreductases
  • Animals
  • Apoptosis / physiology*
  • Cell Nucleolus / metabolism
  • Cells, Cultured
  • Co-Repressor Proteins
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / radiation effects
  • Humans
  • Mice
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphoproteins / radiation effects
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Endopeptidase Complex / radiation effects
  • Protein Transport
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Two-Hybrid System Techniques
  • Ubiquitin / metabolism
  • Ultraviolet Rays

Substances

  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • Alcohol Oxidoreductases
  • Ctbp2 protein, mouse
  • C-terminal binding protein
  • Proteasome Endopeptidase Complex
  • ADP-Ribosylation Factors