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 #
2R01CA132685-06
Application #
8500981
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
2013-06-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$292,156
Indirect Cost
$90,881
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
Liban, Tyler J; Medina, Edgar M; Tripathi, Sarvind et al. (2017) Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family. Proc Natl Acad Sci U S A 114:4942-4947
McGrath, Denise A; Fifield, Bre-Anne; Marceau, Aimee H et al. (2017) Structural basis of divergent cyclin-dependent kinase activation by Spy1/RINGO proteins. EMBO J 36:2251-2262
Ishak, Charles A; Marshall, Aren E; Passos, Daniel T et al. (2016) An RB-EZH2 Complex Mediates Silencing of Repetitive DNA Sequences. Mol Cell 64:1074-1087
Pye, Cameron R; Bray, Walter M; Brown, Elise R et al. (2016) A Strategy for Direct Chemical Activation of the Retinoblastoma Protein. ACS Chem Biol 11:1192-7
Liban, Tyler J; Thwaites, Michael J; Dick, Frederick A et al. (2016) Structural Conservation and E2F Binding Specificity within the Retinoblastoma Pocket Protein Family. J Mol Biol 428:3960-3971
Marceau, Aimee H; Felthousen, Jessica G; Goetsch, Paul D et al. (2016) Structural basis for LIN54 recognition of CHR elements in cell cycle-regulated promoters. Nat Commun 7:12301
Guiley, Keelan Z; Liban, Tyler J; Felthousen, Jessica G et al. (2015) Structural mechanisms of DREAM complex assembly and regulation. Genes Dev 29:961-74
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
Dick, Frederick A; Rubin, Seth M (2013) Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol 14:297-306
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

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