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J. Biol. Chem., Vol. 279, Issue 33, 34938-34947, August 13, 2004

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The Proline-rich Homeodomain Protein Recruits Members of the Groucho/Transducin-like Enhancer of Split Protein Family to Co-repress Transcription in Hematopoietic Cells^*

Tracey E. Swingler, Kirstin L. Bess, Jing Yao¶, Stefano Stifani¶||, and Padma-Sheela Jayaraman, Recipient of a Medical Research Council Career Development Award**

From the Department of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom and ^¶Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada

The proline-rich homeodomain protein (PRH/Hex) is important in the control of cell proliferation and differentiation and in the regulation of multiple processes in embryonic development. We have shown previously that PRH contains two domains that can independently bring about transcriptional repression. The PRH homeodomain represses transcription by binding to TATA box sequences, whereas the proline-rich N-terminal domain of PRH can repress transcription when attached to a heterologous DNA-binding domain. The Groucho/transducin-like enhancer of split (TLE) family of proteins are transcriptional co-repressors that interact with a number of DNA-bound transcription factors and play multiple roles in development. Here we demonstrate that the proline-rich N-terminal domain of PRH binds to TLE1 in vitro and in yeast two-hybrid assays. We show that PRH and TLE proteins are co-expressed in hematopoietic cells and interact in co-immunoprecipitation assays. We demonstrate that TLE1 increases repression by PRH in transient transfection assays and that titration of endogenous TLE proteins by co-expression of Grg5, a natural trans-dominant negative protein, alleviates transcriptional repression by PRH. Finally, we show that a mutation in the PRH N-terminal domain that blocks the PRH-TLE1 interaction in vitro eliminates co-repression. We discuss these results in terms of the roles of PRH and TLE in cell differentiation and development.

Received for publication, April 23, 2004 , and in revised form, June 3, 2004.

^* 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.

Supported by Biotechnology and Biological Sciences Research Council studentships.

^|| Scholar of the Fonds de la Recherche en Sante du Quebec.

^** To whom correspondence should be addressed. Tel.: 44-117-9289708; Fax: 44-117-9288274; E-mail: Sheela.Jayaraman{at}bristol.ac.uk.

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