The phosphoinositide 3-kinase (PI3K) signaling pathway has been highly implicated in human prostatecancer on the basis of frequent loss of the tumor suppressor gene, PTEN in advanced disease. PTENencodes a phosphatase that hydrolyzes the lipid product of PI3K, phosphatidylinositol-3,4,5-trisphosphateand loss of PTEN results in hyperactivation of the protein-Ser/Thr kinase AKT as well as other effectors ofthe PI3K pathway. In this project, we propose to further elucidate components of the PI3K pathway thatcontribute to prostate cancer. In addition, we propose to manipulate endogenous PI3K and PTEN genesand introduce oncogenic mutations of PI3K into mice in order to test the necessity and sufficiency of PI3Kisoforms for development of prostate cancer. This project has three specific aims.
Aim 1 : We will attemptto identify upstream activators of PI3K in human prostate cancer cell lines and in xenograph models byimmunoprecipitating PI3K and identifying co-precipitating proteins. The results of this study should revealprotein-Tyr kinase activators of PI3K that contribute to prostate cancer and that could be targeted fortherapeutic intervention.
Aim 2 : We will introduce oncogenic mutants of the p110a subunit of PI3K intoprostate epithelial tissue by transgene and knockin approaches and determine the effect of these mutationson prostate neoplasia and on gene expression profiles. The results of this study will be compared to ourprevious results with PTEN deletions and with results from mouse models being developed in the Sellers'laboratory (Project 2) and Sawyers' laboratory (Project 3) where activated genes for componentsdownstream of the PI3K pathway are being introduced into the prostate.
Aim 3 : We will introduce a drug-inducible dominant negative form of PI3K to determine the effect of acute inhibition of this pathway onprostate tumors that develop due to loss of PTEN. In addition, we will delete specific genes for catalytic andregulatory subunits of class IA PI3K family in the prostate in the context of prostate-specific PTEN deletion inorder to determine which isoforms of PI3K are critical for tumor formation. The results of this study willpredict whether drugs that target specific PI3K isoforms will be effective in treating this disease.
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