Clinical correlation, in vitro and in rive studies strongly suggest that deregulation of cell cycle progression can result in proliferative disorders including cancer. Cellular proliferation is regulated by mitogenic stimuli and negative growth regulators, 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 cD_-Apl, known to be a growth suppressor, in cell-cycle regulation, as well as 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 ofp12 cD_-Am 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 tiesp12 CDK2-Apl to the TGF- [31 anti-proliferative pathway as a potential negative CDK2 regulator in TGF-131-mediated pRB hypophosphorylation.
The Aims of this application include characterizing the in vivo role ofp12 cDm-Aplas a negative regulator of CDK2 activities and determining how this interaction is involved in the TGF- [31-antiproliferative pathway. With the long-range objective of future clinical applications, Specific Aims include 1) identification of the cis and trans elements responsible for the TGF-131 induction of the p12 gene, 2) examination of the molecular details of p12 cDm-Am in the anti-proliferative effect and 3) validation of in vitro results by examining the expression profiles of p12 cDm-Am, CDK2, TGF- [31 signaling components and pRB in normal and cancer oral epithelia in vivo. ? ?
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