Heat shock proteins (Hsps) play dual roles in cellular biology; they are the first line of defense against cytotoxic stresses, and are tightly integrated into signaling and regulatory pathways under normal growth conditions. A subset of Hsps, including Hsp70 and Hsp90, act as molecular chaperones, and may be required at multiple stages during a substrate protein's lifetime, ranging from biogenesis, localization, and stability, to activation and degradation. Protein chaperones are induced during numerous pathophysiological conditions including ischemia and tumorigenesis, and are known to facilitate stability and activity of oncoproteins such as v-src kinase and the p53 tumor suppressor. The Hsp110 class of chaperones is a poorly understood Hsp70 relative and is present in all eukaryotes, with tissue-specific isoforms of unknown function in humans. The baker's yeast Hsp110 homolog is encoded by the SSE1 and SSE2 genes, and little is known about their function. This proposal seeks to begin to understand the cellular roles of Hsp110 chaperones by asking three specific questions: 1) How does Sse1 operate in partnership with the yeast Hsp70 Ssa1, 2) How does Sse1 participate in signal transduction through the yeast cell integrity pathway in collaboration with the chaperone Hsp90, and 3) How does Sse1 function independently of Hsp90 through interaction with the essential transcriptional complex Mediator? These specific lines of investigation in yeast will serve as a model for predicting which processes Hsp110 may facilitate in mammalian cells. ? ?
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