Prostate cancer progresses from an initially androgen-dependent state to a state of androgen-independence where it no longer is sensitive to androgen ablation therapy. Our hypothesis is that intracellular signal transduction pathways replace the requirement for androgen either by bypassing the Androgen Receptor or by activating the Androgen Receptor so that it functions with little or no androgen or a combination of these. For our first Aim, we propose to analyze the pathways by which Ras- dependent kinases and Protein Kinase A alter growth and gene expression in androgen-responsive prostate cancer cells. For our second Aim we propose to move """"""""upstream"""""""" by analyzing the regulated phosphorylation of the Androgen Receptors and of proteins which bind to this receptor. I.. Protein kinase cascades in the conversion of LNCaP cells to androgen- independence. Growth of prostate cancer cells can be fueled by autocrine and paracrine loops which signal through Ras and/or Protein Kinase A. We will analyze the Ras effector pathways responsible for transforming LNCaP cells to androgen independence, the ways they interact with Protein Kinase A and the changes they undergo as cells progress to androgen independence. II. Intracellular signals which regulate the Androgen Receptor. intracellular regulatory kinases can activate the Androgen Receptor so that it functions transcriptionally in the absence of androgen or is sensitized to low levels of androgen. We will analyze the molecular basis for these effects by examining the regulated phosphorylation of the Androgen Receptor and of its binding partners, and identifying the responsible kinases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA076465-02
Application #
6300590
Study Section
Subcommittee G - Education (NCI)
Project Start
2000-03-08
Project End
2001-01-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$132,463
Indirect Cost
Name
University of Virginia
Department
Type
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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