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.
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
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