Degradation of cellular and viral Fos proteins.
c-Fos proto-oncoprotein is a short-lived transcription factor with oncogenic potential. We have shown that it is massively degraded by the proteasome in vivo under various experimental conditions. Other proteolytic systems including lysosomes and calpains, might, however, also marginally operate on it. Although there is evidence that c-Fos can be ubiquitinylated in vitro, the unambiguous demonstration that ubiquitinylation is necessary for its addressing to 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- and ubiquitin-dependent in vivo. Interestingly, several lines of evidence indicate that the addressing of c-Fos and c-Jun to the proteasome is, at least in part, governed by different mechanisms. c-Fos has been transduced by two murine osteosarcomatogenic retroviruses under mutated forms which are more stable and more oncogenic. The stabilization is not simply accounted for by simple deletion of c-Fos main destabilizer but, rather, by a complex balance between opposing destabilizing and stabilizing mutations. Though mutations in viral Fos proteins confer full resistance to proteasomal degradation, stabilization is limited because mutations also entail sensitivity to an unidentified proteolytic system. This observation is consistent with the idea that Fos-expressing viruses have evolved to ensure control protein levels to avoid high protein accumulation-linked apoptosis. In conclusion, the unveiling of the complex mechanism network responsible for the degradation of AP-1 family members is still at its beginning and a number of issues regarding the regulation of this process and the addressing to the proteasome are still unresolved.
Acquaviva
C
C
Institut de Génétique Moléculaire de Montpellier, UMR5535/IFR24, 1919, Montpellier, France.
Ferrara
P
P
Bossis
G
G
Brockly
F
F
Salvat
C
C
Jariel-Encontre
I
I
Piechaczyk
M
M
D000818:Animals; D005347:Fibroblasts / Q000378:metabolism; D016762:Genes, fos / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D016761:Oncogene Proteins v-fos / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012190:Retroviridae / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*
D009097:Multienzyme Complexes; D016761:Oncogene Proteins v-fos; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014452:Ubiquitins; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease