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）在过去的几年里，我们已经描述了 癌前病变中CDK 4/D型细胞周期蛋白复合物形成的改变 进展这些结果表明，CDK 4在小鼠中起着突出的作用， 皮肤肿瘤发展。基于这些结果，我们开发了几种 表达CDK 4或其同源D型细胞周期蛋白的转基因小鼠， 表皮细胞层。CDK 4动物发生真皮纤维化、表皮纤维化、 增生和肥大。更重要的是，我们的初步结果显示， CDK 4在肿瘤发生中作用。CDK 4的强制过表达， 表皮增加乳头状瘤向鳞状细胞的恶性转化 CDK 4的缺乏完全抑制了肿瘤的发展。 此外，CDK 4过表达导致乳头状瘤的发展，而没有CDK 4的表达。 肿瘤促进剂的应用。根据初步结果， 在这种应用中，pRb磷酸化的缺乏和 TGF-β 1通过CDK 4转基因小鼠的角质形成细胞，我们想提出 本项目的假设如下： I. CDK 4在不依赖于D-型的癌发生中起重要作用 细胞周期蛋白二. CDK 4和TGF-β 1的过度表达之间存在直接联系 表达，其在肿瘤发展过程中具有相关作用。三. CDK 4复合物在肿瘤形成过程中的变化是通过重新分布发生的 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 我们提出了以下具体目标： 1.为了确定CDK 4的催化和非催化功能是否 在肿瘤发展过程中与Ha-ras合作。2.探讨 CDK 4在表皮稳态中的作用及其介导机制。 对TPA和生长因子的过度增殖反应。3.调查是否 TGF-β表达介导CDK 4的一些致癌作用。4.到 研究CDK 4/Survivin复合物在细胞G2期的作用 周期并确定其在恶性进展中的影响。