DEGRADATION OF C-FOS BY THE 26S PROTEASOME IS ACCELERATED BY C-JUN AND MULTIPLE PROTEIN-KINASES

c-Fos is associated with c-Jun to increase the transcription of a numb er of target genes and is a nuclear proto-oncoprotein with a very shor t half-life. This instability of c-Fos may be important in regulation of the normal cell cycle. Here we report a mechanism for degradation o f c-Fos. Coexpression of c-Fos and c-Jun in HeLa cells caused marked i ncrease in the instability of c-Fos, whereas v-Fos, the retroviral cou nterpart of c-Fos, was stable irrespective of the coexpression of c-Ju n. Interestingly, deletion of the C-terminal PEST region of c-Fos, whi ch is altered in v-Fos by a frameshift mutation, greatly enhanced its stability, with loss of the effect of c-Jun on its stability. c-Fos sy nthesized in vitro was degraded by the 26S proteasome in a ubiquitin-d ependent fashion. Simple association with c-Jun had no effect on the d egradation of c-Fos, but the additions of three protein kinases, mitog en-activated protein kinase, casein kinase II, and CDC2 kinase, result ed in marked acceleration of its degradation by the proteasome-ubiquit in system, though only in the presence of c-Jun. In contrast, v-Fos an d c-Fos with a truncated PEST motif were not degraded, suggesting that they escaped from down-regulation by breakdown. These findings indica te a new oncogenic pathway induced by acquisition of intracellular sta bility of a cell cycle modulatory factor.