Department of Cancer Biology
ADP-Ribosylation Factors; Alcohol Oxidoreductases; Animals; Apoptosis; Cell Nucleolus; Cells, Cultured; Colonic Neoplasms; DNA-Binding Proteins; Humans; Mice; Phosphoproteins; Proteasome Endopeptidase Complex; Protein Transport; RNA, Small Interfering; Tumor Suppressor Protein p53; Two-Hybrid System Techniques; Ubiquitin; Ultraviolet Rays
Life Sciences | Medicine and Health Sciences
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.
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Citation: Mol Cell Biol. 2006 Mar;26(6):2360-72. Link to article on publisher's site