Cell cycle dysregulation is a central mechanism in carcinogenesis. Oncogenes and tumor suppressors exert their ultimate mode of action by impinging at strategic points in the cell cycle. Tumor-associated genes interact with key cell cycle regulators in tumor promotion and tumor suppression. The proposed fellowship training provides opportunities for the applicant to examine the molecular, biological, and functional interactions of a recently identified growth suppressor protein, p12(DOC-1), and the cell cycle regulator cyclin-dependent kinase 2 (CDK2), in cell cycle control and oral carcinogenesis. p12(DOC-1) is a growth suppressor identified by differential gene expression screening between normal and malignant oral keratinocytes. p12(DOC-1) negatively regulates DNA replication by associating and mediating phosphorylation of the catalytic subunit of DNA-polymerase alpha/primase (DNA-PP), implicated in the termination mechanism of DNA replication at the end of S phase. Data will be presented to show that p12(DOC-1) interacts with CDK2, a regulator of G1/S transition, S phase progression and DNA replication. We hypothesize that p12(DOC- 1) interacts with CDK2 in cell cycle control and tumor suppression. This hypothesis will be tested by the following three specific aims: 1. to examine the molecular interactions of p12(DOC-1) with CDK2; 2. to examine the interactions of p12(DOC-1) with CDK2 in cell cycle control and 3. to examine the interactions of p12(DOC-1) with CDK2 in oral cancer. The outcome of the proposed work will advance our understanding of cell cycle control and oral carcinogenesis by examining mechanisms of interactions of a novel cell cycle regulator p12(DOC-1) with the well- studied S phase regulator, CDK2.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DE005763-03
Application #
6634595
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Hardwick, Kevin S
Project Start
2002-05-01
Project End
Budget Start
2003-05-01
Budget End
2003-10-19
Support Year
3
Fiscal Year
2003
Total Cost
$26,332
Indirect Cost
Name
Harvard University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Hu, Miaofen G; Hu, Guo-Fu; Kim, Yong et al. (2004) Role of p12(CDK2-AP1) in transforming growth factor-beta1-mediated growth suppression. Cancer Res 64:490-9