Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo
- Ana I. Robles1,6,
- Marcelo L. Rodriguez-Puebla1,
- Adam B. Glick2,
- Carol Trempus3,
- Laura Hansen2,
- Piotr Sicinski4,
- Raymond W. Tennant3,
- Robert A. Weinberg5,
- Stuart H. Yuspa2, and
- Claudio J. Conti1,7
- 1The University of Texas, M.D. Anderson Cancer Center, Science Park–Research Division (SPRD), Smithville, Texas 78957 USA; 2Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892 USA; 3Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 USA; 4Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115 USA; 5The Whitehead Institute for Biomedical Research and Department of Biology, Massachusets Institute of Technology, Cambridge, Massachusetts 02142 USA
Abstract
Cyclin D1 is part of a cell cycle control node consistently deregulated in most human cancers. However, studies with cyclin D1-null mice indicate that it is dispensable for normal mouse development as well as cell growth in culture. Here, we provide evidence thatras-mediated tumorigenesis depends on signaling pathways that act preferentially through cyclin D1. Cyclin D1 expression and the activity of its associated kinase are up-regulated in keratinocytes in response to oncogenic ras. Furthermore, cyclin D1 deficiency results in up to an 80% decrease in the development of squamous tumors generated through either grafting of retroviral ras-transduced keratinocytes, phorbol ester treatment of ras transgenic mice, or two-stage carcinogenesis.
