The cyclin/cdk/pRb pathway is frequently deregulated in human neoplasias. In particular, molecular analysis of human and experimental tumors has shown deregulation of CDK4 and CDK2 kinase activity. Although, CDK4 has been clearly implicated in tumor development, whether increased CDK2 activity is a cause or effect of neoplastic proliferation remains unclear. Recently, we have shown that forced expression of CDK4 under the Keratin 5 promoter, K5-CDK4 mice, results in epidermal hyperplasia and an increased susceptibility to early development of squamous cell carcinomas. Biochemical analysis of K5-CDK4 epidermis and skin tumors show that this phenotype is in part mediated by the sequestration of p27Kip1 and p21Cip1 by CDK4, indirectly activating CDK2 kinase activity. This suggests that increased CDK2/Cyclin E activity observed in various human tumors may in fact play a role in tumor progression. In this case, we hypothesize that overexpression of CDK2 under the keratin 5 promoter should mimic the malignant phenotype observed in K5-CDK4 transgenic mice. To study the involvement of CDK2 in malignant progression we have generated transgenic mice overexpressing CDK2 under the keratin 5 promoter. As expected, K5-CDK2 transgenic mice show increased in vitro CDK2/Cyclin E kinase activity. However, contrary to our initial prediction overexpression of CDK2 does not result in early progression to squamous cell carcinomas under a two stage carcinogenesis protocol. In fact, K5-CDK2 transgenic mice have a reduced number of papillomas in comparison to wild type siblings. This work directly demonstrates in an in vivo setting that increased CDK2 kinase activity does not promote tumor development or progression. Supported by NIH grant CA 90864

[Proc Amer Assoc Cancer Res, Volume 46, 2005]