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）在过去几年中，我们描述了 癌前阶段 CDK4/D 型细胞周期蛋白复合体形成的变化 进展。这些结果表明CDK4在小鼠体内发挥着重要作用。 皮肤肿瘤的发展。基于这些结果，我们开发了几种 表达 CDK4 或其同源 D 型细胞周期蛋白的转基因小鼠 表皮细胞层。 CDK4动物出现真皮纤维化、表皮纤维化 增生和肥大。更重要的是，我们的初步结果表明 CDK4 在肿瘤发展中的作用。 CDK4 的强制过度表达 表皮增加乳头状瘤向鳞状细胞的恶性转化 癌，而 CDK4 的缺乏则完全抑制肿瘤的发展。 此外，CDK4 过度表达会导致乳头状瘤的发展，而无需 肿瘤促进剂的应用。根据获得的初步结果 在本申请中，缺乏 pRb 磷酸化和表达 CDK4转基因小鼠角质形成细胞的TGF-β1，我们想建议 该项目的以下假设： 一、CDK4在不依赖D型的癌变过程中发挥重要作用 细胞周期蛋白。二. CDK4 和 TGF-β 1 的过度表达之间存在直接联系 表达，在肿瘤发展过程中具有相关作用。三． CDK4复合物在肿瘤形成过程中通过重新分布发生变化 细胞周期蛋白、CDK 抑制剂和其他蛋白质的分析，并产生定性和 其激酶活性的定量变化。为了调查这些 我们提出的假设有以下具体目标： 1. 判断CDK4是否具有催化和非催化功能 在肿瘤发展过程中与 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 CDK4 的一些致癌作用。 4. 至 研究 CDK4/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。