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The Role of Ubiquitin-Mediated Proteolysis of Cyclin D in Breast Cancer
Annual summary rept. 1 Apr 2002-31 Mar 2005
TEXAS UNIV HEALTH SCIENCE CENTER AT SAN ANTONIO
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Cyclin D is a positive regulator of the cell cycle and is found to be highly expressed in breast cancer cells. Cyclin D is post transcriptionally regulated by the ubiquitin mediated protein degradation pathway. Cdc34 and SCF are postulated to be the specific E2 and E3 enzymes which target Cyclin D for ubiquitination. It is currently unclear how regulation of the Cdc34-SCF complex may modulate Cyclin Dproteolysis. In this regard, we have studied the regulation of Cdc34 by phosphorylation, by Cdc34-associated proteins and by the interaction with SCF components, Cul1 and Roc1. Our results suggest that the carboxyl-terminal acidic tail domain of Cdc34 is required for efficient in vitro polyubiquitination of p27kip1, though it is not critical for Cdc34 interactions with Cul1 and Roc1 in an in vitro binding assay. The role of Cdc34 phosphorylation on Cul1 and Roc1 binding is still unclear. Currently, our work has focused on identifying the proteins which tightly associate with Cdc34 and which are required for DNA replication initiation in Xenopus egg extracts. We are developing strategies to purify the Cdc34- associated proteins from HeLa cell extracts and from Xenopus egg extracts. We predict that these previously unidentified Cdc34-associated proteins will play an important role in regulating the ubiquitination of cyclin D in vivo.
APPROVED FOR PUBLIC RELEASE