Cellular and viral Fos proteins are degraded by different proteolytic systems

c-Fos proto-oncoprotein is a short-lived transcription factor degraded by t he proteasome in vivo. Its mutated forms expressed by the mouse osteosarcom atogenic retroviruses, FBJ-MSV and FBR-MSV, are stabilized two- and threefo ld, respectively, To elucidate the mechanisms underlying v-Fos(FBJ) and v-F os(FBR) protein stabilization, we conducted a genetic analysis in which the half-lives and the sensitivities to various cell-permeable protease inhibi tors of a variety of cellular and viral protein mutants were measured. Our data showed that the decreased degradation of v-Fos(FBJ) and v-FOSFBR is no t simply explained by the deletion of a c-Fos destabilizing C-terminal doma in. Rather, it involves a complex balance between opposing destabilizing an d stabilizing mutations which are distinct and which include virally-introd uced peptide motifs in both cases. The mutations in viral Fos proteins conf erred both total insensitivity to proteasomal degradation and sensitivity t o another proteolytic system not naturally operating on c-Fos, explaining t he limited stabilization of the two proteins. This observation is consisten t with the idea that FBR-MSV and FBJ-MSV expression machineries have evolve d to ensure controlled protein levels. Importantly, our data illustrate tha t the degradation of unstable proteins does not necessarily involve the pro teasome and provide support to the notion that highly related proteins can be broken down by different proteolytic systems in living cells.