Associate Professor
Office: Shantz 232
Primary Phone: (520) 621-7764
Secondary Phone: (520) 621-5995
Fax: (520) 621-9435
guerrier@u.arizona.edu
Regulation of cellular stress
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 apoptosis, cell proliferation and protein degradation. 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. Recently, our laboratory has collaborated with a crystallography group to produce a model of HspBP1 binding to the ATPase domain of Hsp70. This model has provided new insights on the mechanism of HspBP1 regulation of Hsp70 activity and information that will be used to design mutants for testing of the model. In addition, we have found that HspBP1 in presence in human sera and the levels of antibodies against HspBP1 are elevated in HIV infected patients. These new findings have provided support for the hypothesis that HspBP1 can function both inside and outside the cell.
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| Catherine McLellan | Characterization and domain organization of HspBP1, an inhibitor of Hsp70 activity. | |
Jesus A. Gutierrez |
Identification and characterization of the heat shock response and an inducible Hsp70 gene in bovine skeletal muscle. |
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Xiang Zhou |
Expression of Hsc70/Hsp70 cDNAs in Bacteria and Comparison with Tissue-Isolated Proteins. |
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Articles
Raynes, D. and Guerriero, V. 1998. Inhibition of Hsp70 ATPase Activity and Protein renaturation by a Novel Hsp70-binding Protein. J. Biol. Chem. 273: 32883-32888.
Bloch DB, Gutierrez JA, Guerriero V, Bloch KJ. 1999. Recognition of a dominant epitope in bovine heat‑shock protein 70 in inner ear disease. Laryngoscope 109: (4) 621‑625.
Raynes, D.A. and Guerriero, V. 2000. Isolation and Characterization of Isoforms of HspBP1, an Inhibitor of Hsp70. Biochimica et Biophysica Acta 1490: 203-207.
Guerriero, V. and Raynes, D.A. , inventors; Guerriero and Raynes, assignee. DNA Encoding Proteins that Inhibit Hsp70 Function. United States Patent 6,410,713. 2002 June 25.
Kabani, M., McLellan, C., Raynes, D.A., Guerriero, V., and Brodsky, J.L. (2002). HspBP1, a homologue of the yeast Fes1 abs Sls1 proteins, is an Hsc70 nucleotide exchange factor. FEBS Lett. 531: 339-342.
McLellan CA, Raynes DA, Guerriero V. 2003. HspBP1, an Hsp70 Cochaperone, Has Two Structural Domains and Is Capable of Altering the Conformation of the Hsp70 ATPase Domain. J. Biol. Chem. 278: 19017 - 19022.
Raynes, D.A., Graner, M.A., Bagatell, R. McLellan, C. and Guerriero, V. 2003. Increased Expression of HspBP1 in Tumors. Tumor Biology 24:281-285. .
Bernstein, H., Payne, C.M., Kunke, K., Guerriero, V., Raynes, D. A., Crowley-Weber, C.L., Waltmire, C.N., Dvorakova, K., Holubec., H., Bernstein, C., Vaillancourt, R.R. and Garewal, H. 2004. A proteomic study of deoxycholate induced apoptosis. Carcinogenesis 25: 681-692.
Shomura, Y., Dragovic, Z., Chang, H-C., Tzvetkov, N., Young, J.C., Brodsky, J.L., Guerriero, V., Hartl, F.U. and Bracher, A. Regulation of Hsp70 function by HspBP1: Structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange. 2005. Molecular Cell 17:367-379.
Guerriero, V. and Raynes, D.A. , inventors; Desert Genetics, Inc., assignee. DNA Encoding Proteins that Inhibit Hsp70 Function. United States Patent 6,903,202. 2005 June 7.
Papp, D., Prohászka, Z., Kocsis, J., Füst, G., Bánhegyi, D., Raynes, D.A. and Guerriero, V. 2005. Development of a sensitive assay for the measurement of antibodies against heat shock protein binding protein 1 (HspBP1): Increased levels of anti-HspBP1 IgG are prevalent in HIV infected subjects. J. Med. Vir. 76:464-469.
Guerriero, V. and Raynes, D.A. , inventors; Desert Genetics, Inc. ( Tucson, AZ), assignee. HspBP polypeptides and peptide fragments that bind Hsp 70. United States Patent 6,908,985. 2005 June 21.
Raynes, D.A., Thomson , C.A., Stroster, J., Newton, T., Cuneo, P. and Guerriero, V. Human Sera Contains Detectable Levels of the Hsp70 Cochaperone HspBP1 and Antibodies Bound to HspBP1. (in press). J. Immunoassay and Immunochemistry.