p12CDK2-AP1 in Cell Cycle Control & Oral Carcinogenesis

描述（由申请人提供）：临床相关性、体外和体内研究强烈表明，细胞周期进程失调可导致增殖性疾病，包括癌症。细胞增殖受促有丝分裂刺激和负性生长调节剂调节，而抗增殖信号用于门控对有丝分裂原的增殖反应。这些研究的长期目标是深入了解p12 cD_-Apl在细胞周期调节以及正常和口腔癌发展中的作用，已知p12 cD_-Apl是一种生长抑制因子。了解其通过与细胞周期蛋白依赖性激酶-2（CDK 2）的关联在细胞周期控制中的作用机制可能在癌症的预防和治疗中具有临床应用。形态学、倍增时间和密度依赖性生长研究表明，p12 cD_-Am在体外口腔癌细胞中的再表达与转化表型的逆转有关。最近的数据进一步将p12 CDK 2-Apl与TGF-β 1抗增殖途径联系在一起，作为TGF-β 1介导的pRB低磷酸化中的潜在负CDK 2调节剂。本申请的目的包括表征p12 cDm-Aplas作为CDK 2活性的负调节剂的体内作用，并确定这种相互作用如何参与TGF-β 1-抗增殖途径。随着未来临床应用的长期目标，具体目标包括1）鉴定负责TGF-131诱导p12基因的顺式和反式元件，2）检查p12 cDm-Am在抗增殖作用中的分子细节，以及3）通过检查p12 cDm-Am、CDK 2、CDK 3、CDK 4、CDK 5和CDK 6的表达谱来验证体外结果。TGF-β 1信号传导组分和pRB在正常和癌症口腔上皮中的体内表达。

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.