Targeting of C-terminal binding protein (CtBP) by ARF results in p53-independent apoptosis.
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.
Paliwal
Seema
S
Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Pande
Sandhya
S
Kovi
Ramesh C
RC
Sharpless
Norman E
NE
Bardeesy
Nabeel
N
Grossman
Steven R
SR
D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000429:Alcohol Oxidoreductases; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002466:Cell Nucleolus / Q000378:metabolism; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000528:radiation effects; D021381:Protein Transport; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; C096794:C-terminal binding protein; D046988:Proteasome Endopeptidase Complex; D020727:ADP-Ribosylation Factors