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Molecular and Cellular Biology, March 2006, p. 2360-2372, Vol. 26, No. 6
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.6.2360-2372.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Targeting of C-Terminal Binding Protein (CtBP) by ARF Results in p53-Independent Apoptosis

Seema Paliwal,¹ Sandhya Pande,^1, Ramesh C. Kovi,^1, Norman E. Sharpless,⁴ Nabeel Bardeesy,⁵ and Steven R. Grossman^1,2,3*

Departments of Cancer Biology,¹ Medicine,² Gastrointestinal Cancer Program, University of Massachusetts Medical School and Cancer Center, Worcester, Massachusetts 01605,³ Departments of Medicine and Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599,⁴ MGH Cancer Center, Charlestown, Massachusetts 02129⁵

Received 14 July 2005/ Returned for modification 16 August 2005/ Accepted 23 December 2005

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.

These authors contributed equally to this work.

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