Recently PTEN, a tumor suppressor gene commonly mutant in prostate, has been demonstrated to be a key regulator of the PI3 kinase pathway. The PTEN protein is a phosphatase which, in addition its activity against protein substrates, can dephosphorylate the lipid products of the PI3 kinase family. PTEN removes the 3'-phosphate, which is the found uniquely in the products of PI3 kinase family members. Genetic analyses of PTEN suggest that this PI3 phosphatase activity is ess3ential to its tumor suppressor function. Since these lipids are, among other things, central mediators of central signaling pathways which mediate both cell growth and survival, it is hypothesized that loss of PTEN function should increase both growth and survival. All this excitement has pointed out the need to study PI3 kinase signaling in human prostate tumors and to generate model systems to allow study of the PI3 kinase pathway in prostate tumors in animals. In this grant we will create monoclonal antisera to study the activation state of key PI3 kinase pathway members in actual tumor samples. In addition we will generate mouse models which test the role of the p110 catalytic subunit of PI3 kinase in mouse prostate cancer models. In addition we will generate mouse models which test the role of the p110 kinase is sufficient for prostate tumor formation by generating a transgenic mouse in which an activated mutant allele of p110 is expressed via the probasin which is only active in prostate tissue. We will also test if Pi3 kinase activity is necessary for PTEN mediated tumor formation in mice, To do this we will generate a loxed version of the p110 gene which will allow us to knock out Pi3 kinase function in the prostates which have been engineered to develop prostate tumors in a PTEN dependent fashion.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA089021-02
Application #
6580361
Study Section
Subcommittee G - Education (NCI)
Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2002
Total Cost
$103,677
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
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