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J. Biol. Chem., Vol. 280, Issue 20, 19746-19756, May 20, 2005

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Rb Enhances p160/SRC Coactivator-dependent Activity of Nuclear Receptors and Hormone Responsiveness^*

Éric Batsché, Julien Desroches, Steve Bilodeau, Yves Gauthier, and Jacques Drouin

From the Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada

The retinoblastoma tumor suppressor protein (Rb) is best known as a repressor of genes involved in cell cycle progression. Rb has also been implicated in activation of transcription, in particular by nuclear receptors (NRs) and by differentiation-related transcription factors, but the relevance of this activity is unclear. We show that Rb and the related proteins p107 and p130 enhance the activity of NRs related to NGFI-B (Nur factors) through direct interactions with NGFI-B and SRC-2. Although recruitment of SRC/p160 coactivators to the NGFI-B AF1 domain is independent of Rb, its presence enhances SRC-dependent transcription. Rb potentiation of SRC coactivators is exerted on a subset (Nur factors, hepatocyte nuclear factor-4 (HNF-4), SF-1, and ER) but not all NRs. The levels of Rb-related proteins modulate hormone responsiveness of the NGFI-B-dependent pituitary proopiomelanocortin gene and HNF-4-dependent transcription during enterocyte differentiation. Increased Rb expression upon cell differentiation may promote differentiated functions, at least in part, by potentiation of NR activity.

Received for publication, November 29, 2004 , and in revised form, March 11, 2005.

^* This work was supported in part by grants from the Canadian Institutes of Health Research. 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.

Received fellowships from the Association pour la Recherche Contre le Cancer, the Cancer Research Society, and La Ligue Contre le Cancer.

To whom correspondence should be addressed: Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, 110, Avenue des Pins Ouest, Montréal, Québec H2W 1R7, Canada. Tel.: 514-987-5680; Fax: 514-987-5575; E-mail: jacques.drouin{at}ircm.qc.ca.

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