v-Src generates a p53-independent apoptotic signal

Evasion of apoptosis appears to be a necessary event in tumor progression. Some oncogenes, such as c-myc and ELA, induce apoptosis in the absence of s urvival factors. However, others, such as bcl-2 and v-src, activate antiapo ptotic pathways. For v-Src, these antiapoptotic pathways are dependent on t he function of Ras, phosphatidylinositol (PI) 3-kinase, and Stat3. Here we asked whether v-Src can activate a proapoptotic signal when survival signal ing is inhibited. We show that when the functions of Ras and PI 3-kinase ar e inhibited, v-src-transformed Rat-2 fibroblasts undergo apoptosis, evidenc ed by loss of adherence, nuclear fragmentation, and chromosomal DNA degrada tion. The apoptotic response is dependent on activation of caspase 3. Under similar conditions nontransformed Rat-2 cells undergo considerably lower l evels of apoptosis. Apoptosis induced by v-Src is accompanied by a loss of mitochondrial membrane potential and release of cytochrome c and is blocked by overexpression of bcl-2, indicating that it is mediated by the mitochon drial pathway. However apoptosis induced by v-Src is not accompanied by an increase in the level of p53 and is not dependent on p53 function. Thus v-S rc generates a p53-independent proapoptotic signal.