Somatic mutations and deletions in phosphatase and tensin homologue deleted on chromosome 10 (PTEN) have been identified in a variety of cancers, and in prostate cancer PTEN alterations occur in at least 30% of primary cancers and 63% of metastatic cancers. Since reduced PTEN activity enhances Pl-3 kinase-dependent pathways that promote tumorigenesis. defining the pathways that operate downstream of Pl-3 kinase signaling is essential for understanding transformation mechanisms and for identifying new therapeutic targets. Expression of activated AKT in transgenic mice is not sufficient to phenocopy PTEN loss in prostate, thus additional effectors of Pl-3 kinase signaling are required for prostate cancer to progress beyond prostate intra-epithelial neoplasia (PIN). We hypothesize that the Protein Kinase C-related kinase 1 (PRK1;termed PKN1 after the gene name) is a Pl-3 kinase effector whose properties suggest it cooperates with AKT to transform prostate cancer cells. PKN1 is a direct substrate of PDK1, is over-expressed in human prostate cancer and promotes proliferation in xenograft models, and it modulates androgen receptor (AR) activity by acting as a histone H3 kinase. We show that conditional expression of constitutively active PKN1 in mouse prostate is sufficient to generate murine PIN at 22 weeks.
In Aim 1 we use transgenic mice to characterize prostate cancer phenotypes resulting from PKN1 expression, alone and in combination with AKT. We will determine the role PKN1 plays in transducing tumorigenic effects caused by loss of PTEN.
In Aim 2 we use xenograft and cell culture approaches to determine how PKN1 stimulates tumor growth by exploring its function as a cleavage furrow kinase, and as a factor that modulates the expression and activity of cell cycle regulators.
In Aim 3 we test models for how PKN1 kinase activity promotes gene expression. Including PKN1 phosphorylation of AR and PKN1 generation of specific epigenetic marks. Successful completion of these aims will provide new insights into PTEN/PI-3 kinase signal transduction mechanisms including how PKN1 promotes prostate cell proliferation and how PKN1 regulates AR. We will generate new pre-clinical models of prostate cancer that recapitulate molecular events that occur with loss of PTEN
Prostate cancer is the second leading cause of deaths due to cancer in North American men. Our research is designed to explain how prostate cancer progresses to a state that is resistant to current therapies. This knowledge base will enable the design of new therapeutic strategies.
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