The objective of this proposal is to study the role of cyclins and cyclin related kinases (cdk's) in the mouse skin carcinogenesis model. Based on previous results from our laboratory, we postulate that derangement in the expression of cyclin D1 may be a critical event in the development of chemically induced mouse tumors. Specifically, we propose that aberrant expression of cyclin D1 may be one of the downstream effects of the H-ras mutation that contribute to the initiated phenotype and that further deregulation of the cyclin/cyclin dependent kinase system occurs during tumor progression. The long term goals of this proposal are to define the functions of cyclins in the regulation of normal and neoplastic epidermal proliferation, to provide evidence for its role in the development of chemically induced tumors and to describe the mechanisms involved in the deregulation of cyclin D1 expression in mouse skin tumors.
The Specific Aims of this proposal will be: 1. To study the expression of cyclins and cyclin dependent kinases (cdks) in normal, hyperplastic and neoplastic epidermis. 2. To determine the molecular mechanisms involved in the overexpression of cyclin D1 in chemically induced mouse skin tumors. In this specific aim we will investigate the different possible mechanisms by which cyclin D1 may be overexpressed including the possible role of ras, rearrangements of the cyclin D1 gene, and the role of trisomy of chromosome 7. 3. To demonstrate that overexpression of cyclin D1 has an effect on proliferation and differentiation in normal and initiated keratinocytes. For this purpose we will use two different approaches, i.e., the introduction of an exogenous cyclin D1 gene into normal and initiated epidermal cells and the use of transgenic mice carrying the cyclin D1 gene under the control of an epidermis-specific promoter. The purpose of these experiments are: a) To determine if cells that overexpress cyclin D1 have an altered response to proliferation or differentiation signals; b) to determine the in vivo phenotype of epidermal cells overexpressing cyclin D1; c) To investigate whether cyclin D1 overexpression regulates the expression of other cyclins, cdks or associated proteins; and d) To study the possible cooperation of cyclin D1 with H-ras in the malignant transformation of keratinocytes.
| Miliani de Marval, Paula L; Macias, Everardo; Rounbehler, Robert et al. (2004) Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues. Mol Cell Biol 24:7538-47 |
| Miliani de Marval, Paula L; Macias, Everardo; Conti, Claudio J et al. (2004) Enhanced malignant tumorigenesis in Cdk4 transgenic mice. Oncogene 23:1863-73 |
| Christensen, Laura A; Conti, Claudio J; Fischer, Susan M et al. (2004) Mutation frequencies in murine keratinocytes as a function of carcinogenic status. Mol Carcinog 40:122-33 |
| Gavrielides, M Veronica; Frijhoff, Anita F; Conti, Claudio J et al. (2004) Protein kinase C and prostate carcinogenesis: targeting the cell cycle and apoptotic mechanisms. Curr Drug Targets 5:431-43 |
| Frijhoff, Anita F W; Conti, Claudio J; Senderowicz, Adrian M (2004) Advances in molecular carcinogenesis: current and future use of mouse models to screen and validate molecularly targeted anticancer drugs. Mol Carcinog 39:183-94 |
| Rounbehler, Robert J; Rogers, Pamela M; Conti, Claudio J et al. (2002) Inactivation of E2f1 enhances tumorigenesis in a Myc transgenic model. Cancer Res 62:3276-81 |
| Rodriguez-Puebla, Marcelo L; Miliani de Marval, Paula L; LaCava, Margaret et al. (2002) Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation. Am J Pathol 161:405-11 |
| Russell, Jamie L; Powers, John T; Rounbehler, Robert J et al. (2002) ARF differentially modulates apoptosis induced by E2F1 and Myc. Mol Cell Biol 22:1360-8 |
| Rounbehler, R J; Schneider-Broussard, R; Conti, C J et al. (2001) Myc lacks E2F1's ability to suppress skin carcinogenesis. Oncogene 20:5341-9 |
| Miliani de Marval, P L; Gimenez-Conti, I B; LaCava, M et al. (2001) Transgenic expression of cyclin-dependent kinase 4 results in epidermal hyperplasia, hypertrophy, and severe dermal fibrosis. Am J Pathol 159:369-79 |
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