The serine-threonine kinase Pim-1 is an established oncogene in lymphomagenesis, where it shows dramatic cooperativity in tumor induction with the Myc oncogene. The mechanisms of Pim-1-induced tumorigenicity and the basis for its cooperativity with Myc are largely unknown. Recent studies have shown that Pim-1 is overexpressed in a significant proportion of human prostate cancers and prostatic intraepithelial neoplasia (PIN) lesions. We have recently found that chronic overexpression of Pim-1 in human prostate and breast epithelial cell lines leads to chromosomal instability. Our hypothesis is that Pim-1 overexpression dysregulates expression of mitotic molecules including Cyclin B1, disrupting accurate chromosomal segregation and cytokinesis, culminating in chromosomal instability (CIN). CIN is a common feature of human malignancies, and plays a major role in the generation of genetic abnormalities in tumors. In this proposal, our goals are to elucidate the mechanisms of regulation of Cyclin B1 and mitotic checkpoint molecules by Pim-1 and to establish the role of these molecular alterations in Pim-1-induced chromosomal instability and tumorigenesis. In addition, we will establish and characterize a novel prostate-specific Pim-1 transgenic mouse model to validate these ideas in vivo. Work will be conducted according to the following Specific Aims:
Aim 1 : To elucidate the mechanism(s) underlying altered mitotic regulation and CIN in Pim-1 overexpressing cells.
Aim 2 : To elucidate the roles of Pim-1 and Pim-1-induced chromosomal instability in prostate tumorigenesis by using human prostate cell lines and transgenic mice.
Aim 3 : To test the hypothesis that Pim-1 and Myc cooperate to promote prostate tumorigenesis through the use of human prostate cell lines and transgenic mice. These studies should enhance our understanding of the molecular basis for genomic instability in prostate cancer, establish if Pim-1 is a valid molecular target for prostate cancer therapy and generate new models with relevance to the human disease.
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