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

P12DOC-1

• 批准号: 6634595
• 负责人: MIAOFEN G HU
• 金额: $ 2.63万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6634595
• 关键词: DNA replication; carcinogenesis; cell cycle; cell growth regulation; cyclin dependent kinase; growth inhibitors; human tissue; keratinocyte; neoplasm /cancer genetics; oral pharyngeal neoplasm; postdoctoral investigator; protein protein interaction; tissue /cell culture

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.

细胞周期失调是肿瘤发生的中心机制。癌基因和肿瘤抑制因子通过影响细胞周期中的战略节点发挥其最终的作用模式。肿瘤相关基因与关键的细胞周期调节因子相互作用，促进肿瘤生长和抑制肿瘤生长。拟议的奖学金培训为申请者提供了机会，以研究最近发现的生长抑制蛋白p12(DOC-1)和细胞周期调节因子细胞周期蛋白依赖激酶2(CDK2)在细胞周期控制和口腔癌发生中的分子、生物和功能相互作用。P12(DOC-1)是一种生长抑制因子，通过对正常和恶性口腔角质形成细胞差异表达基因的筛选发现。P12(DOC-1)通过结合和介导DNA聚合酶α/启动子酶催化亚单位(DNAPP)的磷酸化来负向调节DNA复制，参与了S期末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转换、S期进展和DNA复制的调节者。我们假设p12(DOC-1)与CDK2在细胞周期控制和肿瘤抑制中相互作用。这一假说将通过以下三个具体目标得到验证：1.研究p12(DOC-1)与CDK2的分子相互作用；2.研究p12(DOC-1)与CDK2在细胞周期调控中的相互作用；3.研究口腔癌中p12(DOC-1)与CDK2的相互作用。这项工作的结果将通过研究一种新的细胞周期调节因子p12(DOC-1)和研究得很好的S周期调节因子CDK2的相互作用机制来促进我们对细胞周期控制和口腔癌发生的理解。