The overall goal of this research project is to elucidate in molecular detail the function and regulation of retinoblastoma (Rb) pocket proteins. Rb and its homologs p107 and p130 are key cell- cycle control proteins that are disrupted in many cancers. A molecular picture of pocket protein function is therefore important for understanding mechanisms of tumorigenesis and for designing cancer chemotherapeutics. Pocket proteins bind E2F transcription factors and other regulatory proteins on chromatin to control cell-cycle gene expression. Cyclin-dependent kinase (Cdk) phosphorylation inactivates pocket proteins by disrupting these complexes. This proposal aims to determine the structures of pocket proteins and their complexes with functional protein partners. The structural insights will be applied to understand how pocket protein interactions are specific and how they are modulated by multisite Cdk phosphorylation. It is anticipated that these studies will provide fundamental new concepts for understanding mechanisms of tumorigenesis and strategies for treating cancers that result from deregulated cell-cycle control mechanisms.
Tumor cells invariably have defects in the biochemical mechanisms that regulate cell growth and division, so understanding how these processes work is vital to understanding cancer. This project aims to develop a molecular picture of how a family of cell-cycle regulators known as the retinoblastoma pocket proteins function.
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|Rubin, Seth M (2013) Deciphering the retinoblastoma protein phosphorylation code. Trends Biochem Sci 38:12-9|
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|Burke, Jason R; Deshong, Alison J; Pelton, Jeffrey G et al. (2010) Phosphorylation-induced conformational changes in the retinoblastoma protein inhibit E2F transactivation domain binding. J Biol Chem 285:16286-93|
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