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

Basbous, J.; Chalbos, D.; Hipskind, R.; Jariel-Encontre, I.; Piechaczyk, M.

Mol Cell Biol

2007-06 / vol 27 / pages 3936-50


Fra-1, a transcription factor that is 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 nontransformed cells and to elucidate how it is altered in cancer cells. We report that the intrinsic instability of Fra-1 depends on a single destabilizer contained within the C-terminal 30 to 40 amino acids. Two serines therein, S252 and S265, are phosphorylated by kinases of the Erk1/2 pathway, which compromises protein destruction upon both 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 G(0)/G(1)-to-S-phase transition. Finally, our study offers further insights into the signaling-regulated expression of the other Fos family proteins.

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Humans; Animals; Amino Acid Sequence; Molecular Sequence Data; Phosphorylation; Cell Line; Protein Structure, Tertiary; Sequence Alignment; Proteasome Endopeptidase Complex/*metabolism; Cell Cycle/physiology; Serine/metabolism; Proto-Oncogene Proteins c-fos/genetics/*metabolism; MAP Kinase Signaling System/*physiology; Ubiquitin/*metabolism; Mitogen-Activated Protein Kinase 1/genetics/*metabolism; Mitogen-Activated Protein Kinase 3/genetics/*metabolism; Neoplasms/*metabolism; Threonine/metabolism

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