Cyclin Dependent Kinase4 in Chemical Carcinogenesis

化学致癌作用中的细胞周期蛋白依赖性激酶4

• 批准号: 6699375
• 负责人: MARCELO Luis RODRIGUEZ-PUEBLA
• 金额: $ 26.08万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-28 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6699375
• 关键词: chemical carcinogenesis; cyclin dependent kinase; cyclins; enzyme activity; enzyme induction /repression; enzyme inhibitors; gene targeting; genetically modified animals; guanine nucleotide binding protein; laboratory mouse; phorbols; protein protein interaction; skin neoplasms; transforming growth factors

DESCRIPTION:(PROVIDED BY APPLICANT) In the last few years, we have described alterations in CDK4/D-type cyclins complex formations during the premalignant progression. These results showed that CDK4 plays a prominent role in mouse skin tumor development. Based on these results, we have developed several transgenic mice that express CDK4, or their cognate D-type cyclins in the basal cell layer of epidermis. CDK4 animals developed dermal fibrosis, epidermal hyperplasia and hypertrophy. More important, our preliminary results showed an effect of CDK4 in neoplastic development. Forced overexpression of CDK4 in epidermis increased malignant conversion of papillomas to squamous cell carcinomas, whereas the lack of CDK4 completely inhibits tumor development. Moreover, CDK4 overexpression results in papilloma development without the application of tumor promoter. Based on the preliminary result obtained for this application, the lack of pRb phosphorylation and the expression of TGF-beta1 by keratinocytes of CDK4 transgenic mice, we would like to propose the following hypotheses for this project: I. CDK4 plays an essential role in carcinogenesis that is independent of D-type cyclins. II. A direct link exists between overexpression of CDK4 and TGF-beta 1 expression, which has a relevant role during the neoplastic development. III. Changes of CDK4 complexes during the neoplastic process occur by redistribution of cyclins, CDK-Inhibitors and other proteins and results in qualitative and quantitative changes in their kinase activities. To investigate these hypotheses we proposed the following specific aims: 1. To determine whether the catalytic and non-catalytic function of CDK4 collaborate with Ha-ras during neoplastic development. 2. To investigate the role of CDK4 in epidermal homeostasis and the mechanism that mediates it. hyperproliferative response to TPA and growth factors. 3. To investigate if TGF-beta expression mediates some of the oncogenic roles of CDK4. 4. To investigate the roles of CDK4/survivin complexes in the G2 phase of the cell cycle and determine its influence in the malignant progression.

描述：（由申请人提供）在过去的几年中，我们已经描述了 在预签名期间CDK4/D型环蛋白复合物的改变 进展。这些结果表明，CDK4在小鼠中起重要作用 皮肤肿瘤发育。基于这些结果，我们开发了几个 表达CDK4的转基因小鼠或基础上的同源D型细胞周期蛋白 表皮细胞层。 CDK4动物出现了皮肤纤维化，表皮 增生和肥大。更重要的是，我们的初步结果显示 CDK4在肿瘤发育中的影响。强迫CDK4的过表达 表皮增加了乳头状瘤向鳞状细胞的恶性转化 癌，而缺乏CDK4完全抑制了肿瘤的发展。 此外，CDK4的过表达导致乳头状瘤发育没有 肿瘤启动子的应用。基于获得的初步结果 此应用，缺乏PRB磷酸化和 CDK4转基因小鼠的角质形成细胞的TGF-BETA1，我们想提出 该项目的以下假设： I. CDK4在癌变中起着至关重要的作用，而与D型无关 细胞周期蛋白。 ii。 CDK4和TGF-BETA 1之间存在直接链接 表达，在肿瘤发育中具有相关作用。 iii。 肿瘤过程中CDK4复合物的变化通过重新分布发生 细胞周期蛋白，CDK抑制剂和其他蛋白质，并导致定性和 其激酶活性的定量变化。调查这些 假设我们提出了以下具体目的： 1。确定CDK4的催化和非催化功能是否 在肿瘤开发过程中与HA-RAS合作。 2。调查 CDK4在表皮稳态中的作用及其介导的机制。 对TPA和生长因子的高增殖反应。 3。调查是否 TGF-β表达介导CDK4的一些致癌作用。 4 研究CDK4/Survivin复合物在细胞G2相中的作用 循环并确定其在恶性进展中的影响。