Cyclin Dependent Kinase4 in Chemical Carcinogenesis

描述：(申请人提供)在过去的几年里，我们描述了 CDK4/D型细胞周期蛋白复合体在癌前病变中的变化 进步。这些结果表明，CDK4在小鼠体内起着显著的作用。 皮肤肿瘤的发展。基于这些结果，我们开发了几个 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 增生性肥大。更重要的是，我们的初步结果显示 CDK4在肿瘤发生发展中的作用CDK4在卵巢癌中的强制过表达 表皮促进乳头状瘤向鳞状细胞的恶性转化 而CDK4的缺乏则完全抑制肿瘤的发展。 此外，CDK4的过度表达会导致乳头状瘤的发展，而不是 促癌剂的应用。根据所获得的初步结果， 这一应用，缺乏pRb的磷酸化和表达 CDK4转基因小鼠角质形成细胞中转化生长因子-β1的表达 关于该项目的以下假设： I.CDK4在非D型致癌中发挥重要作用 旋风队。CDK4和转化生长因子-β1的过度表达之间存在直接联系 在肿瘤的发生发展过程中起着相关的作用。三. CDK4复合体在肿瘤过程中的变化是通过再分布发生的 细胞周期蛋白、细胞周期蛋白依赖性激酶抑制剂和其他蛋白质的结合 它们的激酶活性发生了定量的变化。为了调查这些 假设我们提出了以下具体目标： 1.确定CDK4的催化和非催化功能 在肿瘤开发期间与Ha-ras合作。2.调查 CDK4在表皮动态平衡中的作用及其机制。 对TPA和生长因子的过度增殖反应。3.调查是否 转化生长因子-β的表达介导了CDK4的部分致癌作用。4.至 研究CDK4/Survivin复合体在细胞G2期的作用 并确定其在恶性进展中的影响。

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.