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All cells contain a set of proteins known as heat stress proteins (Hsps) that provide protection from various environmental stresses such as elevated temperatures, exposure to heavy metals and hypoxia. The levels of these proteins increase when cells are exposed to stresses and the increased levels help the cells survive. These proteins are named according to their molecular weight. The most studied of these proteins have molecular weights of approximately 70kDa and are therefore called the Hsp70-related family of stress proteins. Hsp70 helps the cell survive stresses by binding to partially denatured proteins and assisting to refold these proteins into more stable native structures.
The importance of Hsp70 as a cellular regulator has dramatically increased over the years due to its association with a number of other cellular processes including protein refolding, apoptosis, cell proliferation and protein degradation. Misfolded proteins are a characteristic of some neuromuscular diseases and therefore studies are focused on understanding the regulation of Hsp70 activity on protein refolding. In addition, elevated Hsp70 levels have been reported in a number of different types of cancer and lowering these levels causes cancer cells to undergo apoptosis. Therefore, understanding the regulation of Hsp70 will provide information on the regulation of a diverse number of cellular activities and will have importance in both basic as well as applied medical research. The long term goal of this laboratory is to understand how other proteins can regulate Hsp70.
This laboratory has discovered a novel Hsp70 inhibitory protein called HspBP1. In vitro studies have revealed that HspBP1 binds to and inhibits Hsp70 by removal of bound nucleotide. Further studies have shown that HspBP1 is the most abundant Hsp70 cochaperone in tissues and cells and is elevated in a number of tumors. Our laboratory has collaborated with a crystallography group to produce a model of HspBP1 binding to the ATPase domain of Hsp70.
In addition, we have found that HspBP1 is present in human sera and therefore an extracellular role for this protein has been suggested. We have reported that levels of HspBP1 are elevated in both the tumors and sera from breast cancer patients. Recently we have shown that HspBP1 can bind to the outside of cells and that extracellular HspBP1 stimulates phosphorylation of the EGF receptor. These new findings have provided support for the hypothesis that HspBP1 can function both inside and outside the cell. Current research is focused on the function of extracellular HspBP1 in cancer cell growth.
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