Clinical correlation, in vitro and in vivo studies strongly suggest that deregulation of cell-cycle progression can result in proliferative disorders including cancer. Mitogenic stimuli and negative growth regulators regulate cellular proliferation, while anti-proliferative signals serve to gate the proliferative response to mitogens. The long-term goal of these studies is to gain insight into the role of p12 cDk2-ap1, known to be a growth suppressor, in cell-cycle regulation, and normal and oral cancer development. Understanding its mechanism of action in cell-cycle control via its association with cyclin-dependent kinases- 2 (CDK2) may have clinical applications in the prevention and treatment of cancer. Re-expression of p12 c1) raAel in oral cancer cells in vitro is associated with reversion of transformation phenotypes, as indicated by morphological, doubling time and density-dependent growth studies. Recent data further tie p12 cDm-Ael to the TGF-beta1 anti-proliferative pathway as a CDK2 negative regulator in TGF- [31-mediated hypophosphorylation.
The Aims of this application include characterizing the in vivo role of p12 CDK2-API as a negative regulator of CDK2 activities and determining how this interaction is involved in the TGF-beta1-antiproliferative pathways With the long-range objective of future clinical applications, Specific Aims include 1) identification of the cis and trans elements responsible for the TGF-beta1 induction of the p12 gene, 2) examination of the molecular details of an in vivo role for p12CDK2-API and the anti-proliferative effect and 3) validation of in vitro results by examining the expression profiles of p12 cDrdAm, CDK2, TGF-beta1 signaling components and pRB in normal and cancer oral epithelia in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014857-04
Application #
7034547
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Shirazi, Yasaman
Project Start
2003-07-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$323,954
Indirect Cost
Name
University of California Los Angeles
Department
Dentistry
Type
Schools of Dentistry
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kim, Jeffrey J; Khalid, Omar; Vo, Sheynie et al. (2012) A novel regulatory factor recruits the nucleosome remodeling complex to wingless integrated (Wnt) signaling gene promoters in mouse embryonic stem cells. J Biol Chem 287:41103-17
Deshpande, Amit M; Khalid, Omar; Kim, Jeffrey J et al. (2012) Cdk2ap2 is a novel regulator for self-renewal of murine embryonic stem cells. Stem Cells Dev 21:3010-8
Wong, D T W; Kim, J J; Khalid, O et al. (2012) Double edge: CDK2AP1 in cell-cycle regulation and epigenetic regulation. J Dent Res 91:235-41
Kim, Yong; Deshpande, Amit; Dai, Yanshan et al. (2009) Cyclin-dependent kinase 2-associating protein 1 commits murine embryonic stem cell differentiation through retinoblastoma protein regulation. J Biol Chem 284:23405-14
Deshpande, Amit M; Dai, Yan-Shan; Kim, Yong et al. (2009) Cdk2ap1 is required for epigenetic silencing of Oct4 during murine embryonic stem cell differentiation. J Biol Chem 284:6043-7
Kim, Yong; McBride, Jim; Kimlin, Lauren et al. (2009) Targeted inactivation of p12, CDK2 associating protein 1, leads to early embryonic lethality. PLoS One 4:e4518
Figueiredo, M L; Dayan, S; Kim, Y et al. (2006) Expression of cell-cycle regulator CDK2-associating protein 1 (p12CDK2AP1) in transgenic mice induces testicular and ovarian atrophy in vivo. Mol Reprod Dev 73:987-97
Peng, Hui; Shintani, Satoru; Kim, Yong et al. (2006) Loss of p12CDK2-AP1 expression in human oral squamous cell carcinoma with disrupted transforming growth factor-beta-Smad signaling pathway. Neoplasia 8:1028-36
Kim, Yong; McBride, Jim; Zhang, Rong et al. (2005) p12(CDK2-AP1) mediates DNA damage responses induced by cisplatin. Oncogene 24:407-18
Figueiredo, Marxa L; Kim, Yong; St John, Maie A R et al. (2005) p12CDK2-AP1 gene therapy strategy inhibits tumor growth in an in vivo mouse model of head and neck cancer. Clin Cancer Res 11:3939-48

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