1. ¹Department of Carcinogenesis, Science Park Research Division, MD Anderson Cancer Center, Smithville, TX, USA
2. ²Center for Comparative Medicine and Translational Research, Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
3. ³Department of Molecular and Cellular Oncology, MD Anderson Cancer Center, Houston, TX, USA

Correspondence: Assistant Professor ML Rodriguez-Puebla, Center for Comparative Medicine & Translational Research, Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University – CVM, 4700 Hillsborough Street, Raleigh, NC 27606, USA. E-mail: marcelo_rodriguez-puebla@ncsu.edu

⁴These authors contributed equally to this work.

Received 23 November 2005; Revised 11 July 2006; Accepted 28 July 2006; Published online 18 September 2006.

Abstract

D-type cyclins are components of the cell-cycle engine that link cell signaling pathways and passage throughout G1 phase. We previously described the effects of overexpression cyclin D1, D2 or D3 in mouse epidermis and tumor development. We now asked whether cyclin D2 and/or cyclin D3 play a relevant role in ras-dependent tumorigenesis. Here, we described the effect of cyclin D3 and cyclin D2 overexpression in mouse skin tumor development. Notably, overexpression of cyclin D3 results in reduced tumor development and malignant progression to squamous cell carcinomas (SCC). Biochemical analysis of keratinocytes shows that overexpression of cyclin D3 results in strong reduction of cyclin D2 and its associated kinase activity. Furthermore, we found that reinstatement of cyclin D2 level in the cyclin D3/cyclin D2 bigenic mice results in a complete reversion of the inhibitory action of cyclin D3. Supporting these results, ablation of cyclin D2 results in reduced tumorigenesis and malignant progression. On the other hand, overexpression of cyclin D2 results in an increased number of papillomas and malignant progression. We conclude that cyclin D3 and cyclin D2 play opposite roles in mouse skin tumor development and that the suppressive activity of cyclin D3 is associated with cyclin D2 downregulation.