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Regulation of Hsp70-Mediated Cyclin D1 Destruction in Breast Cancer

Hsp70 介导的细胞周期蛋白 D1 破坏在乳腺癌中的调控

基本信息

批准号：
9286118
负责人：
Andrew William Truman
金额：
$ 44.03万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9286118
关键词：
Affect Alzheimer&apos s Disease Binding Binding Proteins Biological Process Breast Cancer Cell CDK4 gene Carrier Proteins Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Proteins Cell Cycle Regulation Cell Cycle Stage Cells Client Cues Cyclin D1 Cyclin-Dependent Kinases Cyclins Development Disease Down-Regulation Effectiveness Genetic Transcription Growth Heat-Shock Proteins 70 Homologous Gene Housekeeping Huntington Disease Malignant Neoplasms Mammalian Cell Mediating Mediator of activation protein Membrane Modification Molecular Biology Molecular Chaperones Neurodegenerative Disorders Oncoproteins Organism Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Post-Translational Protein Processing Predisposition Process Proliferating Protein C Protein Family Protein Isoforms Proteins Proteomics Publishing Regulation Research Role Signal Transduction Signaling Molecule Site Specificity System Techniques Transcriptional Regulation Ubiquitin Work Yeasts anti-cancer therapeutic cancer cell cancer therapy cancer type cyclin G1 falls in vivo inhibitor/antagonist insight kinase inhibitor malignant breast neoplasm multicatalytic endopeptidase complex novel novel therapeutics protein aggregation protein degradation protein folding protein transport response synergism

项目摘要

Project Summary Hsp70 is a universally conserved molecular chaperone that performs a variety of functions in the cell including protein folding of both newly synthesized and denatured proteins, protein transport across membranes and disaggregation of oligomerized proteins. Research has primarily focused on how Hsp70 function specificity arises through regulation of a) expression of Hsp70, b) isoform differences in the Hsp70 protein family and c) the variety of co-chaperone proteins that bind to the Hsp70 molecule. Despite the identification of several phosphorylation sites on both yeast and mammalian Hsp70 through global proteomic screens, the biological function of these remains unclear. All organisms require correct coordination of the cell cycle to grow and proliferate. Misregulation of cell cycle progression can result in either cell inviability or cancer. Progression of the cell from G1 to G2 requires the activity of cyclin-dependent kinase (CDK) CDK4. The critical activity of CDK4 is regulated by binding to cyclin proteins such as Cyclin D1, which rises and falls in abundance periodically through the cell cycle. Because of the important role of Cyclin D1 in cell cycle control, misregulation of Cyclin D1 activity (through increased transcription or stability) is often observed in cancer cells. Any strategy that lowers Cyclin D1 activity in cells may form the basis of novel anticancer therapies. Our recent studies have determined that phosphorylation of a single site on Hsp70 regulates chaperone function by altering both co-chaperone and client protein interactions. In particular, we have shown that increased Hsp70 phosphorylation promotes Cyclin D1 destruction. In this proposal, we expect to gain further mechanistic insight into how Hsp70 phosphorylation can alter cell cycle progression by downregulating the levels of Cyclin D1 and other important cell cycle proteins. We propose to use both molecular biology and state-of-the-art mass spectrometric techniques in breast cancer cells to achieve the aims of the objectives in our proposal. Understanding the regulation of Hsp70 phosphorylation in mammalian cells will provide us with a completely novel way to target chaperone activity. Hsp70 activity may be suppressed using specific phosphatase/kinase inhibitors. It may be possible to target specific `client' proteins though alteration of Hsp70 phosphorylation status and specific Hsp70 phospho-species may have a higher susceptibility to inhibitors. The scope of this work has broad implications for a variety of diseases associated with both the cell cycle and molecular chaperone function, including many types of cancer and neurodegenerative illnesses caused by protein aggregation (Huntington's disease, Alzheimer's disease and Creutzfeld-Jakob disease).

项目总结