The Role of Ubiquitin-Mediated Proteolysis of Cyclin D in Breast Cancer

Abstract

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTESOriginal contains colored plates: ALL DTIC reproductions will be in black and white. ABSTRACTCyclin D is a positive regulator of the cell cycle and is found to be highly expressed in breast cancer cells. Cyclin D is posttranscriptionally 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. SUBJECT TERMS

State-independent contextuality with identical particles

“…In this article, we address the problem of whether SIC correlations can be obtained for physical systems of indistinguishable particles. Recently, Srikanth and Gangopadhyay [28] have speculated that the stateindependency of quantum contextuality might be lost in this case. Their argument is based of the impossibility of symmetrizing a specific proof of state-independent contextuality for a two-qubit system.…”