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processes in human diseases,

The primary focus of research in the Mivechi Laboratory addresses the regulation and function of mammalian heat shock transcription factors (HSFs) HSF1, HSF2, and HSF4 in cellular stress responses. A second more recent focus has been to study the cellular processes via which organelle-specific molecular chaperones (cytosolic, mitochondrial, and endoplasmic reticulum-resident heat shock proteins) mediate the host response to environmental stressors and the role of these processes in human diseases, including cancer. One approach to this problem has focused on the function of these proteins in knockout mouse models. To this effect, in collaboration with Dr. Moskofidis (GRU Cancer Center), several knockout mouse strains (using a conventional or conditional gene-targeted strategy) in which heat shock factors (hsf1, hsf2, hsf4, heat shock factor binding protein 1) or heat shock proteins (HSPs) of interest (e.g., hsp70.1, hsp70.3, hsc70, hsp25, Hsp110, grp75, grp78, grp94, grp170, sil1) can be globally or cell-specifically inactivated. Research with these animal models over the past several years has fully validated the predicted fundamental roles of the HSP70/HSP90 chaperone machineries and of HSFs in tumor biology, as well as their essential function in embryonic development and in the progression of human diseases associated with defective protein processing and folding. This is best exemplified by their earlier and ongoing studies that have demonstrated a dramatically reduced susceptibility of mice with genetic inactivation of hsf1 to tumor formation induced by chemical carcinogens (liver cancer), or driven by oncogenic signals RAS or ErbB2 (breast, lung cancer types), or by mutant p53 and PTEN (T-ALL and AML). Moreover, several tumor types, including liver, breast, and skin, exhibit a remarkable sensitivity to targeted inactivation of HSPs including HSP70/HSC70 and GRP94. The widespread activation of HSFs, and in particular HSF1, and elevated expression of several HSPs have been shown to be associated with disease progression in patients with cancers such as breast, colon, lung, and hepatocellular carcinomas. This information suggests that these quality control proteins might be useful biomarkers to predict progression of earlystage tumors. In particular, HSF1 and selected chaperone proteins are also attractive therapeutic targets for advanced tumors. Based on existing expertise and their current research results, a high priority of the Mivechi research program will be the promotion of cancer-related translational research. Thus, there is good expectation that applying appropriate drug screening approaches to isolate small molecules that are inhibitors or activators of molecular chaperones or modulators of HSF1 will provide opportunities for translation of discoveries to applied knowledge for therapeutics in cancer. In summary, the overall goal of the program is to promote the development of an integrated program of basic and preclinical research with the ultimate goal of improving clinical outcome of cancer and other related human diseases.