Cyclin dependent kinases (Cdks) are key regulators of cell proliferation in organisms ranging from yeast to man. Composed of a catalytic subunit and a requisite positive regulatory subunit known as a cyclin, Cdk activities regulate all of the major cell cycle transitions. It is not surprising therefore that recent data implicate derangement of Cdks and their regulators in human malignancy. This project has the broad goal of investigating the functions of human Cdks and key Cdk regulatory proteins in the hope that the knowledge gained will shed light on the transition to malignancy and offer new insights for therapy. Targeted for scrutiny will be cyclins A, D and E, Cdk inhibitors p16, p21 and p28, and the small Cdk associated proteins CksHs1 and CksHs2. Two types of approach will be employed. The first will be based on conditional ectopic expression of cyclins and other key regulatory proteins. Manipulating the timing and level of expression of these proteins will allow the identification of downstream targets and the de termination of whether accumulation is sufficient and rate-limiting for function. The second approach will utilize antisense strategies to ablate specific cyclins and regulatory proteins. In this manner the essentially of specific gene products of interest can be assessed. In addition, biochemical analysis of cells targeted by antisense will allow the accurate determination of the consequences of eliminating a single regulatory element thus identifying downstream signaling pathways that are perturbed.
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