Kinase Independent Functions of Cyclin D1 Which Contribute to its Oncogenic Potential In Vivo

摘要

Cyclin D1, an important cell cycle regulator, is a potent oncogene in several tumor types, including breast cancer. The most well understood function of cyclin D1 is to bind and activate cdks 4 and 6. One target of these kinases is pRb. Upon phosphorylation, pRb is inactivated, and cells pass from G1 into S phase. We and others have demonstrated that cyclin Dl has other functions, many of which are independent of kinase activity in vitro. In vivo demonstration of kinase independent functions of cyclin D1 may help elucidate the underlying mechanisms of cyclin D1 oncogenicity. To determine whether cyclin Dl has important kinase-independent functions in vivo, we are generating a cyclin D1 K112E knock-in mouse. This single base change results in a cyclin that can bind to, but not activate the kinase partner. As the locus will be left almost undisturbed, we expect that the mutant allele will be expressed in a normal manner. The phenotype of the mouse will be analyzed to determine whether any of the phenotypes of the cyclin D1 -/- mouse are rescued. This analysis will allow dissection of how the kinase-independent functions of cyclin D1 contribute to development, proliferation and oncogenesis in vivo.