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

P12DOC-1

• 批准号: 6516375
• 负责人: MIAOFEN G HU
• 金额: $ 5.44万
• 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/6516375
• 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重要机制。癌基因和肿瘤抑制因子通过在细胞周期中的关键点发生碰撞来发挥其最终作用模式。肿瘤相关基因与肿瘤促进和肿瘤抑制中的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机会，以检查最近确定的生长抑制蛋白，p12（DOC-1）和细胞周期调节因子细胞周期蛋白依赖性激酶2（CDK 2）的分子，生物学和功能的相互作用，在细胞周期控制和口腔癌。p12（DOC-1）是通过在正常和恶性口腔角质形成细胞之间进行差异基因表达筛选而鉴定的生长抑制因子。p12（DOC-1）通过介导DNA聚合酶α/引发酶（DNA-PP）催化亚基的磷酸化负调控DNA复制，参与DNA复制在S期结束时的终止机制。数据将显示p12（DOC-1）与CDK 2相互作用，CDK 2是G1/S转换，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CDK 2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CDK 2的分子相互作用; 2.检测p12（DOC-1）与CDK 2在细胞周期调控中的相互作用;检测p12（DOC-1）与CDK 2在口腔癌中的相互作用。拟议的工作的结果将推进我们的理解细胞周期控制和口腔癌通过检查一种新的细胞周期调节剂p12（DOC-1）的相互作用的机制与充分研究的S期调节剂，CDK 2。