Cyclin E is a critical cell cycle regulatory protein. At the same time, deregulation of cyclin E expression has been linked to carcinogenesis both in human patients and in mouse models. The current proposal constitutes an ongoing project aimed at gaining understanding into how cyclin E is normally regulated and to elucidate the mechanisms whereby cyclin E expression becomes deregulated and promotes carcinogenesis, respectively. The proposal is divided into three specific aims, the first of which addresses the mechanism of cyclin E degradation in cultured cells and in mice. The role of specific phosphorylation sites on cyclin E will be explored as well as the contribution of a new SCF protein ubiquitin ligase defined by the F-box protein hCdc4. The second specific aim is targeted at the mechanism whereby deregulation of cyclin E confers genomic instability, likely to be a contributing factor in cyclin E-mediated carcinogenesis. Two hypotheses will be explored in detail: that deregulation of cyclin E impairs DNA replication by interfering with pre-replication complex assembly and that elevated cyclin E levels in mitosis block the metaphase-anaphase transition by inhibiting the essential mitotic protein ubiquitin ligase known as APC. The final specific aim seeks to gain a better understanding of the link between cyclin E deregulation and carcinogenesis. Mouse models will be employed to determine if cyclin E promotes carcinogenesis by accelerating loss of heterozygosity (LOH) at tumor suppressor loci. It is hoped that these investigations will provide insights that will ultimately lead to improved prognosis and therapy.
Showing the most recent 10 out of 33 publications
