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J. Biol. Chem., Vol. 282, Issue 41, 29902-29909, October 12, 2007

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Regulation of E2F1 Function by the Nuclear Corepressor KAP1^*

Chuangui Wang¹, Frank J. Rauscher, III, W. Douglas Cress, and Jiandong Chen²

From the Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612 and The Wistar Institute, Philadelphia, Pennsylvania 19104

KAP1 is a nuclear corepressor with conserved domains for RING finger, B boxes, leucine zipper helical coiled-coil region, plant homeo domain finger, and bromo domain. The plant homeo domain finger and bromo domain of KAP1 cooperatively function as a transcription repression domain by recruiting the histone deacetylase complex NuRD and histone H3 lysine 9-specific methyltransferase SETDB1. Here we report that KAP1 binds the E2F1 transcription factor in a retinoblastoma protein (pRb)-independent fashion and inhibits E2F1 activity. KAP1 stimulates formation of E2F1-HDAC1 complex and inhibits E2F1 acetylation. Ectopic expression of KAP1 represses E2F1 transcription and apoptosis functions independent of pRb. Depletion of endogenous KAP1 in pRb-deficient Saos2 cells by RNA interference increases E2F1 acetylation level, stimulates E2F1 transcriptional activity, and sensitizes apoptosis response to DNA damage. Therefore, KAP1 contributes to the negative regulation of E2F1 and may serve as a partial backup to prevent E2F1-mediated apoptosis in the absence of pRb.

Received for publication, June 11, 2007 , and in revised form, July 24, 2007.

^* This work was supported by grants from the National Institutes of Health (to J. C. and W. D. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Institute of Biomedicine, East China Normal University, Shanghai 20062, China.

² To whom correspondence should be addressed: H. Lee Moffitt Cancer Center, MRC3057A, 12902 Magnolia Dr., Tampa, FL 33612. Tel.: 813-903-6822; Fax: 813-903-6817; E-mail: jiandong.chen{at}moffitt.org.

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