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.
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