Abstract 3891: Reduced tumor formation by forced expression of cyclin-dependent kinase 6 in mouse epidermis

Abstract

Abstract The Cyclin-Dependent kinases (CDKs) are a family of essential serine-threonine kinases that are cell cycle regulated by association with cyclins at specific time-points during the cell cycle. Specifically, D-type cyclins form complexes and activate CDK4 and CDK6. We have previously determined that overexpression of CDK4 in mouse epidermis increases malignant progression in chemically induced skin tumors. In order to study the role of CDK6 in squamous epithelial tissues, we generated transgenic mice overexpressing CDK6, driven by the regulatory sequence of the keratin 5 promoter (K5CDK6). Keratinocytes from K5CDK6 mice have similar levels of proliferation compared to wild type mice, however, contrary to the role of CDK4 in mouse skin tumorigenesis, forced expression of CDK6 results in strong reduction of the multiplicity (papillomas per mouse) and incidence of skin tumors. Tumors derived from K5CDK6 or the wild type sibling show no histological differences nor changes in the rate of malignant progression, suggesting that CDK6 expression affects early stages of skin carcinogenesis. Our previous results have also shown that CDK6 preferentially binds to cyclin D3, which overexpression also decreases tumor development in mouse epidermis. Interestingly, lack of Cyclin D1 produces similar phenotype upon chemical carcinogenesis treatment. Thus, we hypothesize that overexpression of Cyclin D3 or CDK6 in a Cyclin D1-null background should synergize with the reduced tumor development previously observed in cyclin D1-null mice. As expected, a lower number of tumors were found in K5-cyclin D3/cyclin D1−/− compound mice compared to cyclin D1−/− siblings. Thus, we hypothesized that the reduced tumor development observed in these mice is a result of the CDK6/Cyclin D3 complex activity. Consequently, K5-CDK6/cyclin D3−/− compound mice are being generated to investigate whether CDK6-associated tumor inhibition depends on cyclin D3 expression. Only in few cases, CDK6 has been associated with tumorigenesis as compared to CDK4 and CDK2, in particular, no association of CDK6 with epidermal tumors has been reported so far. We propose that CDK6/cyclin D3 complexes play an important role in maintaining normal epidermal homeostasis. Therefore we speculate that upregulation of one or both of its components will block tumor development which could be use as a therapeutic approach. Supported by NIH grant CA116328. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3891.