GROWTH FACTOR-DEPENDENT SURVIVAL OF RODENT FIBROBLASTS REQUIRES PHOSPHATIDYLINOSITOL 3-KINASE BUT IS INDEPENDENT OF PP70(S6K) ACTIVITY

A variety of mammalian cells undergo apoptosis when deprived of growth factors, but the intracellular signaling pathways responsible for cel l survival remain to be characterized. In the present study, we have i nvestigated the role of PI 3-kinase and pp70(S6K) in growth factor-dep endent survival of rodent fibroblasts. As previously reported for PC12 pheochromocytoma cells, Rat-1 and REF52 cells underwent apoptosis fol lowing either serum-deprivation or treatment with the PI 3-kinase inhi bitors wortmannin and LY294002. In contrast, NIH3T3 and BALB 3T3 cells were resistant to apoptosis induced by either serum-deprivation or PI 3-kinase inhibition. It thus appears that PI 3-kinase is specifically required to prevent apoptosis of fibroblast that are dependent upon g rowth factors survival. Consistent with this role of PI 3-kinase, seru m and growth factors maintained steady state levels of PI 3-kinase act ivity that rapidly decreased following serum-deprivation. Serum and gr owth factors similarly maintained a steady state level of pp70(S6K), w hich is thought to be activated downstream of PI 3-kinase. However, in hibition of pp70(S6K) activation by rapamycin failed to induce apoptos is in either Rat-1 or PC12 cells. Cell survival thus appears to requir e a PI 3-kinase signaling pathway that is independent of pp70(S6K) act ivation.