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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132685-07
Application #
8668907
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Knowlton, John R
Project Start
2008-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$282,909
Indirect Cost
$87,672
Name
University of California Santa Cruz
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Burke, Jason R; Liban, Tyler J; Restrepo, Tamara et al. (2014) Multiple mechanisms for E2F binding inhibition by phosphorylation of the retinoblastoma protein C-terminal domain. J Mol Biol 426:245-55
Rubin, Seth M (2013) Deciphering the retinoblastoma protein phosphorylation code. Trends Biochem Sci 38:12-9
Schachter, Miriam Merzel; Merrick, Karl A; Larochelle, Stephane et al. (2013) A Cdk7-Cdk4 T-loop phosphorylation cascade promotes G1 progression. Mol Cell 50:250-60
Dick, Frederick A; Rubin, Seth M (2013) Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol 14:297-306
Balog, Eva Rose M; Burke, Jason R; Hura, Greg L et al. (2011) Crystal structure of the unliganded retinoblastoma protein pocket domain. Proteins 79:2010-4
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
Hirschi, Alexander; Cecchini, Matthew; Steinhardt, Rachel C et al. (2010) An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein. Nat Struct Mol Biol 17:1051-7