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Functional analysis of the cdk inhibitor p21 and its regulation by cell cycle dependent degradation


Research objectives and content
Progression through the mammalian cell cycle is controlled by the tightly regulated activity of cyclin-dependent kinases (cdk's). Both positive and negative regulators of these kinases classify as oncogenes and tumor suppressor genes, respectively, and dysregulation of these activities is implicated in a variety of malignancies. The novel class of cdk inhibitors appears to negatively regulate G1 phase specific cdk's and, thereby, inhibit cell cycle progression. p21 is a cdk inhibitor specifically implicated in mediation of the DNA damage checkpoint, cellular senescence, and differentiation (for review see Harper & Elledge, 1996). Since p21's very complex mode of function is not yet understood and conflicting data on its features were published my research proposal is focused on elucidating the activity of p21 in more detail under different physiological conditions. My well characterized set of newly established monoclonal antibobies to human p21 will hopefully give new insights in target preferences and function of p21 under various conditions. Presently, my major interest is p21's regulation on the level of protein stability, since my own preliminary results demonstrate a quick turnover of the protein, which is mediated by the ubiquitin-proteasome protein degradation machinery. The post-translational regulation by altered protein stability appears to be an essential control mechanism of key cell cycle regulators.
Harper, W., and Elledge, S.,; Cdk inhibitors in development and cancer. Cur.Op.Gen.& Dev., 6: 56-64, 1996.
Training content (objective, benefit and expected impact)
Independent working conditions, a good panel of applyable methods and creative scientific discussions are basics for successful
research-standards in the Department of Cell Cycle and Cancer. I expect to produce a conclusive and contributory study on p21 resulting in a Ph.D thesis after approximately three years. The quality standard of this study will be of great importance for further applications in other laboratories.
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Strandboulevarden 49
2100 Koepenhagen

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