p12CDK2-AP1 in Cell Cycle Control & Oral Carcinogenesis

描述(由申请人提供)：临床相关性，体外和在RIVE研究强烈表明，放松细胞周期进程的调控可导致包括癌症在内的增殖性疾病。细胞增殖受有丝分裂刺激和负生长调节剂的调节，而抗增殖信号则起到抑制有丝分裂原的增殖反应的作用。这些研究的长期目标是深入了解p12CD_-APL在细胞周期调节以及正常和口腔癌发展中的作用。通过与细胞周期蛋白依赖性激酶-2(CDK2)的关系了解其在细胞周期调控中的作用机制，可能在癌症的预防和治疗中具有临床应用价值。形态、倍增时间和密度依赖性生长研究表明，p12CD-Am在体外口腔癌细胞中的重新表达与转化表型的逆转有关。最近的数据进一步将p12-CDK2-APL与转化生长因子-[31]抗增殖通路联系在一起，认为在转化生长因子-131介导的pRb低磷酸化过程中，p12-CDK2-APL是一个潜在的负调控因子。这一应用的目的包括表征p12 CDM-Aplas在体内对CDK2活性的负调节作用，并确定这种相互作用如何参与转化生长因子-[31-抗增殖途径]。在未来临床应用的长期目标中，具体目标包括：1)鉴定p12基因诱导的顺式和反式元件；2)检测p12 CDM-Am在抗增殖作用中的分子细节；3)通过检测p12 CDM-Am、CDK2、TGF-[31]信号元件和pRb在活体口腔黏膜上皮中的表达谱来验证体外结果。

DESCRIPTION (provided by applicant): 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.