v-Jun sensitizes cells to apoptosis by a mechanism involving mitochondrial cytochrome C release.

v-Jun shares the ability of the Myc, E1A, and E2F oncogenes to both sustain cell cycle progression and promote apoptosis in the absence of mitogenic stimulation. To gain an insight into the mechanism of apoptosis sensitization, we examined the possible involvement of key regulatory proteins previously implicated in oncogene-induced cell death during v-Jun-induced apoptosis triggered by serum withdrawal. We observed that ectopic expression of the anti-apoptotic Bcl-2 protein, or of two downstream effectors of growth factor signalling, v-PI 3-Kinase and v-Src, partially or completely suppressed apoptosis. Apoptosis was also observed in the presence of serum growth factors when endogenous PI3K activity was blocked using the synthetic inhibitor LY294002, further suggesting an important role for PI3-K in cell survival. Cytochrome C was released into the cytosol of apoptotic v-Jun expressing cells, and this release was inhibited by Bcl-2, suggesting an important role for mitochondrial dysfunction in v-Jun induced apoptosis. In contrast, inhibition of Fas signalling using dominant negative FADD did not inhibit apoptosis, nor was there any evidence for accumulation or activation of p53 in v-Jun transformed cells. Consistent with this latter observation, inhibition of p53 function by HPV16 E6 protein had no effect on v-Jun induced cell death. Taken together, these results suggest that mitochondrial dysfunction is an important component of the mechanism through which v-Jun sensitizes cells to apoptosis, but that the apoptotic signals elicited by v-Jun upstream of the mitochondria do not depend on increased levels of p53 activity or Fas signalling.