Protein kinase reverts C-ζ reverts v-raf transformation of NIH-3T3 cells

We have identified protein kinase C-ζ (PKC-ζ) as a novel suppressor of neoplastic transformation caused by the v-raf oncogene. PKC-ζ overexpression drastically retards proliferation, abolishes anchorage-independent growth, and reverts the morphological transformation of v-raf-transformed NIH-3T3 cells. The molecular basis for this effect appears to be a specific induction of junB and egr-1 expression, triggered synergistically by PKC-ζ via a Raf/Mek/MAPK-independent mechanism and v-raf. junB-promoter/CAT assays revealed that PKC-ζ directly targets the junB promoter. The induction of junB and egr-1 is linked to the v-raf transformation-suppressing effect of PKC-ζ as constitutive expression of junB and egr-1 but not of c-jun also abolishes anchorage-independent growth of v-raf-transformed NIH-3T3 cells. Moreover, junB overexpression leads to a retardation of proliferation in these cells. PKC-ζ interferes with the serum inducibility of an AP-1 reporter plasmid in v-raf-transformed NIH-3T3 cells, indicating that PKC-ζ antagonizes transformation and proliferation by down-modulating AP-1 function via induction of junB. In summary, our data suggest that PKC-ζ counteracts v-raf transformation by modulating the expression of the transcription factors junB and egr-1.