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 E1A, induce apoptosis in the absence of survival factors. However, others, such as bcl-2 and v-src, activate antiapoptotic pathways. For v-Src, these antiapoptotic pathways are dependent on the function of Ras, phosphatidylinositol (PI) 3-kinase, and Stat3. Here we asked whether v-Src can activate a proapoptotic signal when survival signaling is inhibited. We show that when the functions of Ras and PI 3-kinase are inhibited, v-src-transformed Rat-2 fibroblasts undergo apoptosis, evidenced by loss of adherence, nuclear fragmentation, and chromosomal DNA degradation. The apoptotic response is dependent on activation of caspase 3. Under similar conditions nontransformed Rat-2 cells undergo considerably lower levels 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 mitochondrial 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-Src generates a p53-independent proapoptotic signal.
Webb
B L
BL
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.
Jimenez
E
E
Martin
G S
GS
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D016895:Culture Media, Serum-Free; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000276:immunology / Q000378:metabolism; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts; D005456:Fluorescent Dyes / Q000378:metabolism; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008858:Microscopy, Phase-Contrast; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011498:Protein Precursors / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000590:Amino Acid Chloromethyl Ketones; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D008869:Microtubule-Associated Proteins; D015688:Oncogene Protein pp60(v-src); D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011498:Protein Precursors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D018631:ras Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C505410:Casp3 protein, rat