Alterations in Cell Cycle Regulation in Mouse Skin Tumors

Abstract

The connection between cell cycle and cancer has become obvious in as much as it is considered that dysregulated cellular proliferation is a hallmark of cancer. In many studies, the dysregulation of the cyclin-cdk-cki network has been reported in experimental animal and human tumors, but to our knowledge a complete profile of alterations in regulatory molecules in any tumor model system is lacking. In this study, we assessed the expression of various cyclins, cyclin dependent kinases, and cyclin kinase inhibitors in chemically induced squamous papillomas in SENCAR mouse skin. Western blot analysis data showed a significant upregulation of cyclins (31, 6, 19, and 12 folds elevation for cyclin-D1, D2, E, and A, respectively) in tumors compared to the normal skin. The protein expression of the cdk (1, 2, and 4) was also found to be elevated in tumors compared to normal skin (33 fold for cdk1, 14 fold for cdk2, and 9 fold for cdk4). In tumors, compared to the normal skin, a significant increase in the level of protein expression of p27 and p57 (4 and 3 fold, respectively) was evident. In normal skin, p16 and p21 were not detectable but significant expression of these proteins was detected in tumors. Taken together, these data provide evidence that cell cycle deregulation in G1-phase is a critical event during the course of two stage skin carcinogenesis. This may have relevance to epithelial cancers in general.