MECHANISM OF SERINE/THREONINE KINASE SURVIVAL PROMOTION

University Of Illinois At Chicago, Chicago IL

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Abstract

Serum and certain growth factors promote survival and inhibit apoptosis, but the mechanism by which this is achieved is unclear. Activated forms of Ras, Raf and Src are transforming but do not deliver a survival signal upon serum withdrawal, whereas inhibition of PI3kinase accelerated apoptosis and an activated form of the S/T kinase Akt, a downstream effector of PI3K, blocked apoptosis. The ability of Akt to promote survival was dependent upon its kinase activity. PI3K and Akt appear to be components of a pathway that transduces a survival signal that ultimately blocks Ced3/ICE protease activity. This proposal focusses on delineating the mechanism(s) by which Akt promotes survival concentrating on three aspects. (1) Does Akt deliver a survival signal by inactivating 4E-BP1, the repressor of protein translation? (2) Does Akt intervene in the apoptosis cascade at the level of Bcl-2 family members, integrity of mitochondria, caspase activity or Ced-4/Apaf-1? (3) Does Akt promote survival by increasing cell-cell adhesion and/or intracellular levels of b-catenin via inhibition of GSK3?