Cyclin D3 deficiency inhibits skin tumor development, but does not affect normal keratinocyte proliferation

Rearrangement and amplification of the D-type cyclin genes have been reported in human cancer. Previous studies have demonstrated that Ras-mediated skin tumorigenesis depends on pathways that act through cyclin Dl and D2; however, the role of cyclin D3 remains unknown. The present study demonstrates that cyclin D3 ablation does not affect keratinocyte proliferation, but instead increases apoptosis levels in the bulge region of the hair follicle. Consequently, cyclin D3 ablation reduces skin papilloma development in a Ras-dependent carcinogenesis model. Previous results revealed that cyclin D3 preferentially binds to cyclin-dependent kinase 6 (CDK6) in mouse keratinocytes and transgenic expression of CDK6 (K5CDK6 mice) inhibits skin tumor development. Thus, we hypothesized that the inhibitory effect of CDK6 is dependent on cyclin D3 expression. To test this hypothesis, a mouse model that overexpresses CDK6 and does not express cyclin D3 (K5CDK6/cyclin D3(-/-) compound mouse) was developed. Biochemical analysis of the epidermis of K5CDK6/cyclin D3(-/-) mice revealed that cyclin D3 ablation.resulted in increased expression of cyclin Dl protein, with a consequent elevation in the level of CDK6/cyclin Dl and CDK4/cyclin Dl complexes. These findings were concurrent with the increase skin papilloma malignant progression observed in K5CDK6/cyclin D3(-/-) mice. In summary the absence of cyclin D3 led to fewer number of papillomas in cyclin D3-ablated mice than in the wild-type owing to increased apoptosis, suggesting that alterations in