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J. Biol. Chem., Vol. 283, Issue 22, 15201-15208, May 30, 2008

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The LIM-only Protein FHL2 Regulates Cyclin D1 Expression and Cell Proliferation^*

Charlotte Labalette¹, Yann Nouët², Joëlle Sobczak-Thepot^¶, Carolina Armengol³, Florence Levillayer, Marie-Claude Gendron^||, Claire-Angélique Renard, Béatrice Regnault^**, Ju Chen, Marie-Annick Buendia, and Yu Wei⁴

From the Unité d'Oncogenèse et Virologie Moléculaire and ^**PT "Puce à ADN," Institut Pasteur, 28 Rue du Dr. Roux, 75015 Paris, France, Inserm U579, 28 Rue du Dr. Roux, 75015 Paris, France, ^¶Université Paris VI, CNRS UMR7098, 7 Quai Saint-Bernard, 75005 Paris, France, ^||Institut Jacques Monod, 2 Place Jussieu, 75005 Paris, France, and the Department of Medicine, Institute of Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0613

The LIM-only protein FHL2 acts as a transcriptional modulator that positively or negatively regulates multiple signaling pathways. We recently reported that FHL2 cooperates with CREB-binding protein/p300 in the activation of β-catenin/T cell factor target gene cyclin D1. In this paper, we demonstrate that FHL2 is associated with the cyclin D1 promoter at the T cell factor/CRE site, providing evidence that cyclin D1 is a direct target of FHL2. We show that deficiency of FHL2 greatly reduces the proliferative capacity of spontaneously immortalized mouse fibroblasts, which is associated with decreased expression of cyclin D1 and p16^INK4a, and hypophosphorylation of Rb. Reexpression of FHL2 in FHL2-null fibroblasts efficiently restores cyclin D1 levels and cell proliferative capacity, indicating that FHL2 is critical for cyclin D1 activation and cell growth. Moreover, ectopic cyclin D1 expression is sufficient to override growth inhibition of immortalized FHL2-null fibroblasts. Gene expression profiling revealed that FHL2 deficiency triggers a broad change of the cell cycle program that is associated with down-regulation of several G₁/S and G₂/M cyclins, E2F transcription factors, and DNA replication machinery, thus correlating with reduced cell proliferation. This change also involves down-regulation of the negative cell cycle regulators, particularly INK4 inhibitors, which could counteract the decreased expression of cyclins, allowing cells to grow. Our study illustrates that FHL2 can act on different aspects of the cell cycle program to finely regulate cell proliferation.

Received for publication, January 28, 2008 , and in revised form, March 26, 2008.

^* This work was supported in part by the Association pour la Recherche sur le Cancer and the Comité de Paris of La Ligue contre le Cancer. 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 Supported by the Ecole Normale Supérieure de Lyon.

² Supported by the Cancéropôle Ile-de-France.

³ Supported by the Fondation pour la Recherche Médicale.

⁴ To whom correspondence should be addressed: Unité d'Oncogenèse et Virologie Moléculaire, Institut Pasteur, 28 Rue du Dr. Roux, 75015, Paris, France. Tel.: 33-1-45688851; Fax: 33-1-45688943; E-mail: ywei{at}pasteur.fr.

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