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J. Biol. Chem., Vol. 281, Issue 6, 3172-3181, February 10, 2006

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BRCA1 Affects Lipid Synthesis through Its Interaction with Acetyl-CoA Carboxylase^*

Karen Moreau¹, Eva Dizin¹, Hind Ray², Céline Luquain³, Etienne Lefai, Fabienne Foufelle^¶, Marc Billaud, Gilbert M. Lenoir^||, and Nicole Dalla Venezia⁴

From the CNRS UMR 5201, Laboratoire de Génétique Moléculaire, Signalisation et Cancer, Faculté deMédecine Rockefeller, 69373 Lyon cedex 08, France, INSERM U449-INRA 1235, Faculté deMédecine Laennec, Rue G. Paradin, 69372 Lyon cedex 08, France, ^¶INSERM U671, Centre Biomédical des Cordeliers, Université Paris VI, 15 Rue de l'Ecole de Médecine, 75270 Paris cedex 06, France, and ^||CNRS UMR 8125, Institut Gustave Roussy, Laboratoire de Génétique Oncologique, 39 Rue Camille-Desmoulins, 94805 Villejuif cedex, France

Germ line alterations in BRCA1 (breast cancer susceptibility gene 1) are associated with an increased susceptibility to breast and ovarian cancer. BRCA1 acts as a scaffold protein implicated in multiple cellular functions, such as transcription, DNA repair, and ubiquitination. However, the molecular mechanisms responsible for tumorigenesis are not yet fully understood. We have recently demonstrated that BRCA1 interacts in vivo with acetyl coenzyme A carboxylase (ACCA) through its tandem of BRCA1 C terminus (BRCT) domains. To understand the biological function of the BRCA1·ACCA complex, we sought to determine whether BRCA1 is a regulator of lipogenesis through its interaction with ACCA. We showed here that RNA inhibition-mediated down-regulation of BRCA1 expression induced a marked increase in the fatty acid synthesis. We then delineated the biochemical characteristics of the complex and found that BRCA1 interacts solely with the phosphorylated and inactive form of ACCA (P-ACCA). Finally, we demonstrated that BRCA1 affects lipid synthesis by preventing P-ACCA dephosphorylation. These results suggest that BRCA1 affects lipogenesis through binding to P-ACCA, providing a new mechanism by which BRCA1 may exert a tumor suppressor function.

Received for publication, April 28, 2005 , and in revised form, November 30, 2005.

^* This work was supported by the Ligue Nationale Contre le Cancer of Rhône, the Association pour la Recherche sur le Cancer, and European Commission Grant LSH-M_CT_2004_005272 EXGENESIS. 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 These authors contributed equally to this work. Recipients of fellowships from French Ministry of Research.

² Recipient of a fellowship from the Association pour la Recherche sur le Cancer.

³ Recipient of a fellowship from the Fondation de France.

⁴ To whom correspondence should be addressed: Laboratoire de Génétique Moléculaire, Signalisation et Cancer, CNRS UMR 5201, Faculté de Médecine Rockefeller, 8 Ave. Rockefeller, 69373 Lyon cedex 08, France. Tel.: 33-478-777-213; Fax: 33-478-777 220; E-mail: dalla{at}rockefeller.univ-lyon1.fr.

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