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J. Biol. Chem., Vol. 276, Issue 2, 1578-1584, January 12, 2001
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From the Center for Neuronal Survival, Montreal Neurological
Institute, McGill University, Montreal, Quebec H3A 2B4, Canada
Hairy/Enhancer of split 1 (Hes1) is a mammalian
transcriptional repressor that plays crucial roles in the regulation of
several developmental processes, including neuronal differentiation.
The aim of this study was to elucidate the molecular mechanisms that regulate the transcription repression activity of Hes1. It is shown
here that Hes1 associates with the nuclear matrix, the
ribonucleoprotein network of the nucleus that plays important roles in
transcriptional regulation. Nuclear matrix binding is mediated by the
same Hes1 C-terminal domain that is also required for transcriptional
repression. This domain contains the WRPW motif that acts as a binding
site for the transcriptional corepressor Groucho, which also localizes to the nuclear matrix. Both the nuclear matrix association and transcription repression activity of Hes1 are inhibited by deletion of
the WRPW motif, indicating that Groucho acts as a transcriptional corepressor for Hes1. This corepressor role is not modulated by the
Groucho-related gene product Grg5. In contrast, the Runt-related protein RUNX2, which localizes to the nuclear matrix and interacts with
Groucho and Hes1, can inhibit both the Groucho·Hes1
interaction and the transcription repression ability of Hes1. Together,
these observations suggest that transcriptional repression by Hes1
requires interactions with Groucho at the nuclear matrix and that RUNX proteins act as negative regulators of the repressive activity of
Groucho·Hes1 complexes.
Association with the Nuclear Matrix and Interaction with Groucho
and RUNX Proteins Regulate the Transcription Repression Activity of the
Basic Helix Loop Helix Factor Hes1*
,
*
This work was supported in part by grants from the Cancer
Research Society Inc. (70%) and the Medical Research Council of Canada
(GR-14971) (30%) (to S. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a Studentship from the Medical Research Council of Canada.
§
Supported by a Studentship from the Fonds pour la Formation de
Chercheurs et l'Aide a la Recherche.
¶
Scholar of the Fonds de la Recherche en Sante du Quebec and
Killam Scholar of the Montreal Neurological Institute. To whom correspondence should be addressed: Tel.: 514-398-3946; Fax:
514-398-1319; E-mail: mdst@musica.mcgill.ca.
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