P12DOC-1 & CDK2 IN CELL CYCLE CONTROL & ORAL CANCER

细胞周期失调是癌变的主要机制。癌基因和肿瘤抑制因子通过在细胞周期的策略点上碰撞来发挥其最终的作用模式。肿瘤相关基因在肿瘤促进和肿瘤抑制中与关键细胞周期调节因子相互作用。拟议的奖学金培训为申请人提供了检查最近发现的生长抑制蛋白p12（DOC-1）和细胞周期调节因子周期蛋白依赖性激酶2（CDK2）在细胞周期控制和口腔癌变中的分子，生物学和功能相互作用的机会。p12（DOC-1）是一种生长抑制因子，通过正常和恶性口腔角质形成细胞之间的差异基因表达筛选确定。p12（DOC-1）通过关联和介导DNA聚合酶α /引物酶（DNA- pp）催化亚基的磷酸化，负性调控DNA复制，参与S期结束时DNA复制的终止机制。数据将显示p12（DOC-1）与CDK2相互作用，CDK2是G1/S转变、S期进展和DNA复制的调节因子。我们假设p12（DOC- 1）在细胞周期控制和肿瘤抑制中与CDK2相互作用。这一假设将通过以下三个具体目标进行检验：1。检测p12（DOC-1）与CDK2的分子相互作用；2. 研究p12（DOC-1）与CDK2在细胞周期控制中的相互作用；研究口腔癌中p12（DOC-1）与CDK2的相互作用。通过研究一种新的细胞周期调节剂p12（DOC-1）与已被充分研究的S期调节剂CDK2的相互作用机制，本研究的结果将促进我们对细胞周期控制和口腔癌变的理解。

Cell cycle dysregulation is a central mechanism in carcinogenesis. Oncogenes and tumor suppressors exert their ultimate mode of action by impinging at strategic points in the cell cycle. Tumor-associated genes interact with key cell cycle regulators in tumor promotion and tumor suppression. The proposed fellowship training provides opportunities for the applicant to examine the molecular, biological, and functional interactions of a recently identified growth suppressor protein, p12(DOC-1), and the cell cycle regulator cyclin-dependent kinase 2 (CDK2), in cell cycle control and oral carcinogenesis. p12(DOC-1) is a growth suppressor identified by differential gene expression screening between normal and malignant oral keratinocytes. p12(DOC-1) negatively regulates DNA replication by associating and mediating phosphorylation of the catalytic subunit of DNA-polymerase alpha/primase (DNA-PP), implicated in the termination mechanism of DNA replication at the end of S phase. Data will be presented to show that p12(DOC-1) interacts with CDK2, a regulator of G1/S transition, S phase progression and DNA replication. We hypothesize that p12(DOC- 1) interacts with CDK2 in cell cycle control and tumor suppression. This hypothesis will be tested by the following three specific aims: 1. to examine the molecular interactions of p12(DOC-1) with CDK2; 2. to examine the interactions of p12(DOC-1) with CDK2 in cell cycle control and 3. to examine the interactions of p12(DOC-1) with CDK2 in oral cancer. The outcome of the proposed work will advance our understanding of cell cycle control and oral carcinogenesis by examining mechanisms of interactions of a novel cell cycle regulator p12(DOC-1) with the well- studied S phase regulator, CDK2.