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J. Biol. Chem., Vol. 282, Issue 42, 31046-31059, October 19, 2007

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Heterodimerization with Jun Family Members Regulates c-Fos Nucleocytoplasmic Traffic^*

From the Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, 1919 Route de Mende, Montpellier F-34293, France

c-Fos proto-oncoprotein forms AP-1 transcription complexes with heterodimerization partners such as c-Jun, JunB, and JunD. Thereby, it controls essential cell functions and exerts tumorigenic actions. The dynamics of c-Fos intracellular distribution is poorly understood. Hence, we have combined genetic, cell biology, and microscopic approaches to investigate this issue. In addition to a previously characterized basic nuclear localization signal (NLS) located within the central DNA-binding domain, we identified a second NLS within the c-Fos N-terminal region. This NLS is non-classic and its activity depends on transportin 1 in vivo. Under conditions of prominent nuclear localization, c-Fos can undergo nucleocytoplasmic shuttling through an active Crm-1 exportin-independent mechanism. Dimerization with the Jun proteins inhibits c-Fos nuclear exit. The strongest effect is observed with c-Jun probably in accordance with the relative stabilities of the different c-Fos:Jun dimers. Retrotransport inhibition is not caused by binding of dimers to DNA and, therefore, is not induced by indirect effects linked to activation of c-Fos target genes. Monomeric, but not dimeric, Jun proteins also shuttle actively. Thus, our work unveils a novel regulation operating on AP-1 by demonstrating that dimerization is crucial, not only for active transcription complex formation, but also for keeping them in the compartment where they exert their transcriptional function.

Received for publication, April 3, 2007 , and in revised form, July 31, 2007.

^* This work was supported in part by grants from the Association pour la Recherche sur le Cancer and the Action Concertée Incitative Biologie Cellulaire of the French Ministry of Research. 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 a fellowship from the Association pour la Recherche sur le Cancer.

² M. P.'s laboratory is an Equipe labellisée of the French Ligue Nationale contre le Cancer. To whom correspondence may be addressed: Tel.: 33-4-67-61-36-68; Fax: 33-4-67-04-02-31; E-mail: marc.piechaczyk{at}igmm.cnrs.fr.

³ To whom correspondence may be addressed: Tel.: 33-4-67-61-36-68; Fax: 33-4-67-04-02-31; E-mail: isabelle.jariel{at}igmm.cnrs.fr.

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