Cyclin-dependent kinases (CDKs) are key regulators of cellular proliferation of eukaryotes. The CDKs are the ultimate targets of growth stimulatory and inhibitory signals. Deregulation of CDK activities has been found in a variety of human cancers. Thus, to learn how CDKs execute their functions is not only necessary for elucidating the processes that control cellular proliferation, but also provides insights into mechanisms of tumorigenesis. The long-term objective of our research is to understand the detailed molecular mechanisms by which cell division cycle is regulated in human cells and to understand how the perturbation of normal cell cycle control results in tumorigenesis. The regulation of CDKs has been extensively studied, nevertheless, relatively little is known about how these CDKs regulate specific cell cycle events, largely because physiological substrates of these kinases have not been adequately characterized. To understand how cyclin E-Cdk2, a key CDK required for the G1-to-S phase transition, executes its function in vivo, we developed a strategy to isolate potential cyclin E-Cdk2 substrates and identified NPAT as one of the targets of this kinase complex. We and others have shown that NPAT activates histone gene transcription and promotes S phase entry. These results suggest that NPAT plays an important role in the G1-to-S phase transition. Here we propose to investigate the molecular mechanisms of both NPAT function and regulation.
The specific aims of this grant are to: (1) investigate the mechanism by which NPAT coordinates transcriptional histone gene transcription; (2) determine the roles of NPAT in histone gene transcription and G1/S phase transition; (3) study the regulation of NPAT function by cyclin E-Cdk2 kinase. It is not unreasonable to expect that this research may lead to identification of novel targets for cancer diagnosis or therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM065814-01A1
Application #
6572755
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Zatz, Marion M
Project Start
2003-02-01
Project End
2008-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
1
Fiscal Year
2003
Total Cost
$275,625
Indirect Cost
Name
University of Rochester
Department
Genetics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
DeRan, Michael; Pulvino, Mary; Zhao, Jiyong (2011) Assessing G1-to-S-phase progression after genotoxic stress. Methods Mol Biol 782:221-30
DeRan, Michael; Pulvino, Mary; Greene, Eriko et al. (2008) Transcriptional activation of histone genes requires NPAT-dependent recruitment of TRRAP-Tip60 complex to histone promoters during the G1/S phase transition. Mol Cell Biol 28:435-47
Su, Chuan; Gao, Guang; Schneider, Sandra et al. (2004) DNA damage induces downregulation of histone gene expression through the G1 checkpoint pathway. EMBO J 23:1133-43
Zhao, Jiyong (2004) Coordination of DNA synthesis and histone gene expression during normal cell cycle progression and after DNA damage. Cell Cycle 3:695-7
Gao, Guang; Bracken, Adrian P; Burkard, Karina et al. (2003) NPAT expression is regulated by E2F and is essential for cell cycle progression. Mol Cell Biol 23:2821-33