p12CDK2-AP1 in Cell Cycle Control & Oral Carcinogenesis

描述：临床相关性、体外和体内研究强烈表明，放松对细胞周期进程的调控可能导致包括癌症在内的增殖性疾病。有丝分裂刺激和负生长调节因子调节细胞增殖，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已知的生长抑制因子p12CDK2-AP1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的生长研究表明，p12(C1)Raael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 CDM-Ael与转化生长因子-β1抗增殖通路联系在一起，作为转化生长因子-[31]介导的低磷酸化中的CDK2负调控因子。本应用的目的包括确定p12CDK2-API作为CDK2活性的负调控因子在体内的作用，并确定这种相互作用如何参与转化生长因子-β1-抗增殖通路，以及未来临床应用的长期目标，具体目标包括：1)鉴定与转化生长因子-β1诱导p12基因表达有关的顺式和反式元件；2)检测p12CDK2-API在体内的作用和抗增殖作用的分子细节；3)通过检测p12 cDrdAm、CDK2、转化生长因子-β1信号组件和pRB在体内正常口腔黏膜和口腔癌上皮中的表达谱，对体外结果进行验证。

DESCRIPTION: 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.