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J. Biol. Chem., Vol. 282, Issue 20, 15248-15257, May 18, 2007

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A Novel Corepressor, BCoR-L1, Represses Transcription through an Interaction with CtBP^*

Julia K. Pagan, Jeremy Arnold, Kim J. Hanchard, Raman Kumar^¶, Tiziana Bruno^||, Mathew J. K. Jones, Derek J. Richard, Alistair Forrest^**, Amanda Spurdle, Eric Verdin, Merlin Crossley, Maurizio Fanciulli^||, Georgia Chenevix-Trench, David B. Young¹, and Kum Kum Khanna¹²

From the Queensland Institute of Medical Research, 300 Herston Road, Herston 4029, Queensland, Australia, School of Medicine, Central Clinical Division, University of Queensland, Royal Brisbane Hospital, Herston 4029, Queensland, Australia, ^¶Breast Cancer Genetics Group, Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide, South Australia 5000, Australia, ^||Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy, ^**Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia, Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158, and the School of Molecular and Microbial Biosciences, G08, University of Sydney, New South Wales 2006, Australia

Corepressors play a crucial role in negative gene regulation and are defective in several diseases. BCoR is a corepressor for the BCL6 repressor protein. Here we describe and functionally characterize BCoR-L1, a homolog of BCoR. When tethered to a heterologous promoter, BCoR-L1 is capable of strong repression. Like other corepressors, BCoR-L1 associates with histone deacetylase (HDAC) activity. Specifically, BCoR-L1 coprecipitates with the Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its role as a transcriptional repressor. BCoR-L1 also interacts with the CtBP corepressor through a CtBP-interacting motif in its amino terminus. Abrogation of the CtBP binding site within BCoR-L1 partially relieves BCoR-L1-mediated transcriptional repression. Furthermore, BCoR-L1 is located on the E-cadherin promoter, a known CtBP-regulated promoter, and represses the E-cadherin promoter activity in a reporter assay. The inhibition of BCoR-L1 expression by RNA-mediated interference results in derepression of E-cadherin in cells that do not normally express E-cadherin, indicating that BCoR-L1 contributes to the repression of an authentic endogenous CtBP target.

Received for publication, January 9, 2007 , and in revised form, March 20, 2007.

^* This work was supported by Australian Research Council, National Health and Medical Research Council of Australia and the Queensland Cancer Fund. 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 These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 61-7-3362-0338; Fax: 61-7-3362-0105.

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