Cyclin Dependent Kinase4 in Chemical Carcinogenesis

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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.