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Mol. Cell. Biol. doi:10.1128/MCB.01776-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Ubiquitin-independent proteasomal degradation of Fra-1 is antagonized by Erk1/2 pathway-mediated phosphorylation of a unique C-terminal destabilizer

Institut de Génétique Moléculaire de Montpellier, CNRS, 1919 Route de Mende, Montpellier, F-34293, France; Inserm, U540, Montpellier, F-34090, France; University Montpellier I, Montpellier, F-34000, France

^* To whom correspondence should be addressed. Email: marc.piechaczyk{at}igmm.cnrs.fr.

	Abstract

Fra-1, a transcription factor phylogenetically and functionally related to the proto-oncoprotein c-Fos, controls many essential cell functions. It is expressed in many cell types, albeit with differing kinetics and abundances. In cells reentering the cell cycle, Fra-1 expression is transiently stimulated, albeit later than that of c-Fos and for a longer time. Moreover, Fra-1 overexpression is found in cancer cells displaying high Erk1/2 activity and has been linked to tumorigenesis. One crucial point of regulation of Fra-1 levels is controlled protein degradation, the mechanism of which remains poorly characterized. Here we have combined genetic, pharmacological and signaling studies to investigate this process in non-transformed cells and to elucidate how it is altered in cancer cells. We report that intrinsic instability of Fra-1 depends on a single destabilizer contained within the C-terminal 30-40 amino acids. Two serines therein, S252 and S265, are phosphorylated by kinases of the Erk1/2 pathway, which compromises protein destruction both upon normal physiological induction and tumorigenic constitutive activation of this cascade. Our data also indicate that Fra-1, like c-Fos, belongs to a small group of proteins that may, under certain circumstances, undergo ubiquitin-independent degradation by the proteasome. Our work reveals both similitudes and differences between Fra-1 and c-Fos degradation mechanisms. In particular, the presence of a single destabilizer within Fra-1, instead of two that are differentially regulated in c-Fos, explains the much faster turnover of the latter when cells traverse the G0/G1-S transition. Finally, our study offers further insights into the signaling-regulated expression of the other Fos family proteins.

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