v-Jun sensitizes cells to apoptosis by a mechanism involving mitochondrialcytochrome 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 s timulation. To gain an insight into the mechanism of apoptosis sensitizatio n,,ve examined the possible involvement of key regulatory proteins previous ly 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 effecters of growth fac tor signalling, v-PI 3-Kinase and v-Src, partially or completely suppressed apoptosis, Apoptosis was also observed in the presence of serum growth fac tors when endogenous PI3K activity was blocked using the synthetic inhibito r 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 rol e for mitochondrial dysfunction in v-Jun induced apoptosis, In contrast, in hibition of Fas signalling using dominant negative FADD did not inhibit apo ptosis, nor was there any evidence for accumulation or activation of p53 in v-Jun transformed cells. Consistent with this latter observation, inhibiti on 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 upstre am of the mitochondria do not depend on increased levels of p53 activity or Fas signalling.