AKT, A TARGET OF PHOSPHATIDYLINOSITOL 3-KINASE, INHIBITS APOPTOSIS INA DIFFERENTIATING NEURONAL CELL-LINE

Phosphatidylinositol (PI) 3-kinase has been suggested to mediate cell survival, Consistent with this possibility, apoptosis of conditionally (simian virus 40 T-ts) immortalized rat hippocampal H19-7 neuronal ce lls was increased in response to wortmannin, an inhibitor of PI 3-kina se, Downstream effectors of PI 3-kinase include Rac1, protein kinase C , and the serine-threonine kinase Akt (protein kinase IJ). Here, we sh ow that activation of Akt is one mechanism by which PI 3-kinase can me diate survival of H19-7 cells during serum deprivation or differentiat ion, While ectopic expression of mild-type Akt (c-Akt) does not signif icantly enhance survival in H19-7 cells, expression of activated forms of Akt (v-Akt or myristoylated Akt) results in enhanced survival whic h can be comparable to that conferred by Bcl-2. Conversely, expression of a dominant-negative mutant of Akt accelerates cell death upon seru m deprivation or differentiation, Finally, the results indicate that A kt can transduce a survival signal for differentiating neuronal cells through a mechanism that is independent of induction of Bcl-2 or Bcl-x (L) or inhibition of Jun kinase activity.