This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The abundant molecular chaperone Hsp90 is critical for the folding and regulation of a specific set of diverse client proteins involved in cell division and differentiation. In the last few years Hsp90 has emerged as a viable anti-cancer drug target since many oncogenic proteins require Hsp90 for function. As proof of concept, Hsp90 inhibitors slow tumor growth and are currently in Phase II clinical trials. In addition to playing a critical role in the growth of certain tumors, Hsp90 is also required for the development of drug-resistant pathogenic yeast infections caused by Candida albicans, since Hsp90 inhibitors slowed or prevented drug resistance. Thus it seems likely that Hsp90 is required for the function of key proteins involved in C. albicans pathogenicity and the adaptation to drug treatment. The overall goals of this proposal are to determine how Hsp90 function differs depending on the life stage of C. albicans. The driving hypothesis is that during the switch to the pathogenic growth phase or during development of drug resistance, activities of Hsp90 will be focused on client proteins essential for these specialized functions.
Specific Aim 1. Characterize the cellular events that lead to cleavage of Candida albicans Hsp90. Patients that survive systemic infections of C. albicans have circulating antibodies against a fragment of Hsp90. Additional studies indicate that antibodies against C. ablicans Hsp90 are protective in treating candidiasis. Another laboratory established that when expressed in S. cerevisiae, C. albicans undergoes cleavage to generate the immunogenic fragments. We will use a genetic approach in yeast to identify conditions that alter production of the immunogenic fragments with the goal of making directed mutations in C. ablicans to determine the effect of altered proteolytic cleavage on infection and immunogenicity in mouse models.
Specific Aim 2. Characterize the interaction of Hsp90 with Hbt1, a protein required for polarized morphogenesis in Saccharomyces cerevisiae. During the hyphal transition, C. albicans undergoes polarized morphogeneis and reorganization of the cell wall. We identified an interaction between Hbt1 and Hsp90 containing mutations that cause slow, temperature sensitive growth accompanied by altered morphology. Our hypothesis is that Hsp90 interacts with Hbt1 in cells under limiting growth conditions or in cells undergoing morphological changes. These studies will provide novel information about the functions of Hsp90 and Hbt1 in cellular signaling pathways.
Specific Aim 3. Understanding the similarities and differences in how Hsp90 interacts with diverse client proteins. In conjunction with co-chaperone proteins, Hsp90 interacts with hundreds of diverse proteins. We will determine whether the activity of diverse Hsp90 client proteins is similarly affected by mutations in Hsp90 and co-chaperones.
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