We have previously described cell cycle control alteration in the mouse skin carcinogenesis two-stage model. Based on our previous work and the preliminary results obtained for this application we would like to propose the following overall hypothesis for this project: Cyclin D1 is not essential in ras induced proliferation but is necessary for ras transformation Cyclin D1 has a modulation effect on cell adhesion and cytoskeleton structure Cyclin D2 and D3 have distinctive roles in normal epidermal proliferation as well as in tumor development Dysregulation of cell cycle control in ras transformation requires both, over-expression of cyclin D1 and down-regulation of p27 cdki. To investigate these hypotheses we propose the following specific aims: 1) To study the mechanisms involved in the resistance of ras transformation of cyclin D1 deficient cells. We will investigate the proliferative response to ras signaling in cells deficient in cyclin D1 and/or cyclin D2 using primary cultures of keratinocytes obtained from D1, D2 and double KO as well as in transgene models over-expressing a mutated ras gene. 2) To investigate the role of cyclin D1 in cell adhesion, cytoskeleton structure and its possible role in maintaining a stem cell phenotype. 3) To investigate the role of Cyclin D type cyclin in epidermal homeostasis and its hyperproliferative response to TPA and growth factors. 4) To investigate the role of D-type cyclins and the cdk1 p27 in carcinogenesis. In particular we will evaluate the effects of the over- expression of deficiency of these genes in multi-stage carcinogenesis (initiation, promotion and progression).
| 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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