Multiple degradation pathways for Fos family proteins

Acquaviva, C.; Bossis, G.; Ferrara, P.; Brockly, F.; Jariel-Encontre, I.; Piechaczyk, M.

Ann N Y Acad Sci

2002-11 / vol 973 / pages 426-34


c-Fos protooncoprotein is a short-lived transcription factor with oncogenic potential. It is massively degraded by the proteasome in vivo under various experimental conditions. Those include consititutive expression in exponentially growing cells and transient induction in cells undergoing the G0/G1 phase transition upon stimulation by serum. Though there is evidence that c-Fos can be ubiquitinylated in vitro, the unambigous demonstration that prior ubiquitinylation is necessary for degradation by the proteasome in vivo is still lacking. c-Jun, one of the main dimerization partners of c-Fos within the AP-1 transcription complex, is also an unstable protein. Its degradation is clearly proteasome dependent. However, several lines of evidence indicate that the mechanisms by which it addresses the proteasome are different from those operating on c-Fos. Moreover, genetic analysis has indicated that c-Fos is addressed to the proteasome via pathways that differ depending on the conditions of expression. c-Fos has been transduced by two murine osteosarcomatogenic retroviruses in mutated forms, which are more stable and more oncogenic. The stabilization is not simply accounted for by simple deletion of one of the main c-Fos destabilizers but, rather, by a complex balance between opposing destabilizing and stabilizing mutations. However, although viral Fos proteins have acquired full resistance to proteasomal degradation, stabilization is limited because the mutations they have accumulated, during or after c-fos gene transduction, confer sensitivity to an unidentified proteolytic system(s). This observation is consistent with the idea that fos-expressing viruses have evolved expression machineries to ensure controlled protein levels in order to maintain an optimal balance between prooncogenic and proapoptotic activities of v-Fos proteins.

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Humans; Animals; Amino Acid Sequence; Gene Expression Regulation; Transcription Factors/metabolism; Cell Cycle/physiology; Ubiquitin/metabolism; Proteasome Endopeptidase Complex; Cysteine Endopeptidases/metabolism; Multienzyme Complexes/metabolism; Oncogene Proteins v-fos/*genetics; Peptide Fragments/chemistry; Proto-Oncogene Proteins c-fos/*genetics/*metabolism

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