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J. Biol. Chem., Vol. 280, Issue 33, 29625-29636, August 19, 2005

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H19 mRNA-like Noncoding RNA Promotes Breast Cancer Cell Proliferation through Positive Control by E2F1^*

Nathalie Berteaux, Séverine Lottin¶, Didier Monté||, Sébastien Pinte**, Brigitte Quatannens||, Jean Coll, Hubert Hondermarck, Jean-Jacques Curgy¶¶, Thierry Dugimont||||, and Eric Adriaenssens||||

From the ERI-8 INSERM "Signalisation des Facteurs de Croissance dans le Cancer du Sein, Protéomique Fonctionnelle," UPRES-EA 1033, IFR 118, Université des Sciences et Technologies de Lille (USTL), 59655, Villeneuve d'Ascq, France and CNRS ^||UMR 8117, ^**UMR 8526, and UMR 8527, Institut de Biologie de Lille (IBL), 59021, Institut Pasteur, Lille, France

The imprinted H19 gene has riboregulatory functions. We show here that H19 transcription is up-regulated during the S-phase of growth-stimulated cells and that the H19 promoter is activated by E2F1 in breast cancer cells. H19 repression by pRb and E2F6 confirms the E2F1-dependent control of the H19 promoter. Consistently, we demonstrate by chromatin immunoprecipitation assays that endogenous E2F1 is recruited to the H19 promoter in vivo. The functionality of E2F promoter sites was further confirmed by gel shift and mutagenesis experiments, revealing that these sites are required for binding and promoter response to E2F1 exogenous expression and serum stimulation. Furthermore, we show that H19 overexpression confers a growth advantage on breast cancer cells released from growth arrest as well as in asynchronously growing cells. The H19 knockdown by small interfering RNA duplexes impedes S-phase entry in both wild-type and stably H19-transfected cells. Based on these findings, we conclude that the H19 RNA is actively linked to E2F1 to promote cell cycle progression of breast cancer cells. This clearly supports the H19 oncogenic function in breast tumor genesis.

Received for publication, April 13, 2005 , and in revised form, June 27, 2005.

^* 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.

Recipient of a "Ministère de l'Education Nationale et de la Recherche" and an Association pour la Recherche sur le Cancer (ARC) fellowship.

^¶ Recipient of an ARC fellowship. Present address: INSERM U 354, Bt G8, RN7, 91030 Evry cedex, France.

Recipient of grants from the "Fédération des Groupements des Entreprises Françaises dans la Lutte contre le Cancer (FéGEFLUC)," the "Comités du Nord et de l'Aisne de la Ligue Nationale contre le Cancer," and ARC.

^|||| Both authors contributed equally to this work.

^¶¶ To whom correspondence should be addressed: INSERM-ERI8, UPRES-EA 1033, USTL, SN3, 59655 Villeneuve d'Ascq cedex, France. Tel.: 33-320-43-40-14; Fax: 33-320-43-40-38; E-mail: curgy{at}univ-lille1.fr.

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