Heterodimerization with Jun family members regulates c-Fos nucleocytoplasmic traffic

Malnou, C. E.; Salem, T.; Brockly, F.; Wodrich, H.; Piechaczyk, M.; Jariel-Encontre, I.

J Biol Chem

2007-10-19 / vol 282 / pages 31046-59


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.

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Humans; Transcription, Genetic/*physiology; Animals; Mice; Rats; Hela Cells; Dimerization; Active Transport, Cell Nucleus/physiology; BALB 3T3 Cells; beta Karyopherins/genetics/metabolism; Cell Nucleus/genetics/*metabolism; Cytoplasm/genetics/*metabolism; Karyopherins/genetics/metabolism; Nuclear Localization Signals/genetics/metabolism; Proto-Oncogene Proteins c-fos/genetics/*metabolism; Proto-Oncogene Proteins c-jun/genetics/*metabolism; Receptors, Cytoplasmic and Nuclear/genetics/metabolism; Transcription Factor AP-1/genetics/*metabolism

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