Cyclin D1 Represses STAT3 Activation through a Cdk4-independent Mechanism^*

Frédéric Bienvenu, Hugues Gascan, and Olivier Coqueret

From INSERM EMI-U 9928, Centre Hospitalier Universitaire Angers, 4 rue Larrey, 49033 Angers Cedex, France

STAT3 transcription factors are cytoplasmic proteins that induce gene activation in response to cytokine receptor stimulation. Following tyrosine phosphorylation, STAT3 proteins dimerize, translocate into the nucleus, and activate specific target genes. Activation is transient, and down-regulation of STAT3 signaling occurs within a few hours. In this study, we show that cyclin D1 inhibits STAT3 activation. In co-immunoprecipitation and pull-down assays, cyclin D1 was found to associate with the activation domain of STAT3 upon interleukin-6 stimulation. Overexpression of cyclin D1 inhibited transcriptional activation by STAT3 proteins. This effect was not shared by cyclin E, was independent of association with Cdk4, and was unaffected by inhibitors of Cdk4. Whereas cyclin D1 had no effect on the steady-state level of STAT3 proteins in the cytoplasm, it was found to reduce the STAT3 nuclear level in HepG2 cells. These results suggest a model by which cyclin D1 is part of a feedback network controlling the down-regulation of STAT3 activity and highlight a new activity for this cell cycle regulatory protein.

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^* This work was supported by a fellowship (to F. B.) and a grant from the Ligue Nationale pour la Recherche sur le Cancer ("Equipe Labelisée la Ligue contre le Cancer").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.

To whom correspondence should be addressed. Tel.: 33-2-41-35-47-33; Fax: 33-2-41-73-16-30; E-mail: olivier.coqueret@univ-angers.fr.

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Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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