Fall oncogenic activities of v-Src are mediated by multiple signaling pathways - Ras as an essential mediator for cell survival

Tyrosine kinase oncoproteins cause simultaneous activation of multiple intr acellular signaling pathways. However, the precise mechanisms by which indi vidual pathways induce oncogenesis are not well understood. We have investi gated the roles of individual signaling pathways in v-Src-dependent cell gr owth and survival by inhibiting one particular pathway. v-Src induced const itutive activation of signal transducers and activators of transcription 3 (STAT3), phosphatidylinositol 3-kinase, and Res in murine Ba/F3 cells and l ed to factor-independent proliferation. Dominant-negative mutants of STAT3 (STAT3D) and phosphatidylinositol 3-kinase (Delta p85) inhibited v-Src-depe ndent growth by similar to 60 and similar to 40%, respectively. Moreover, d ominant-negative Res (N17) induced severe apoptosis, which was accompanied by down regulation of Bcl-2 and activation of caspase-3. Although cells ove rexpressing Bcl-2 or caspase-3 inhibitors remained viable even when N17 was expressed, the growth was reduced by similar to 85%. During N17- and STAT3 D-induced growth suppression, expression of cyclin D2, cyclin D3, c-myc, an d c-fos was suppressed by N17, whereas that of cyclin D2, cyclin E, and c-m yc was suppressed by STAT3D, Thus, v-Src-activated Ras and STAT3 are involv ed in distinct but partly overlapping transcriptional regulation of cell cy cle regulatory molecules. These results suggest that the full oncogenic act ivity of v-Src requires simultaneous activation of multiple signalings, in which Ras is particularly required for survival.