Protein Chaperones and Stress Response
in Saccharomyces cerevisiae

Protein molecular chaperones are an essential component of the cellular stress response, as well as key players in protein biogenesis and regulation during normal growth. The chaperone Hsp90 facilitates the function of a number of intrinsically labile key regulatory protein "clients", such as growth control kinases (CDK, Raf) and steroid hormone receptors, and protooncogenic regulators including the Src family of tyrosine kinases and the tumor suppressor p53. Because of its pivotal involvement in cell cycle progression, growth control and signaling, understanding Hsp90 function and regulation is of critical importance. Using the powerful genetics of the single-celled eukaryote, Saccharomyces cerevisiae, the protein kinase Sch9, related to the protein kinase A and B (Akt) families of growth control kinases, was identified as a repressor of Hsp90 chaperone activity, indicating that a regulatory pathway controls Hsp90 function. We are investigating Hsp90 regulation by the Sch9 kinase and the signaling network that governs this pathway to coordinate stress response with cell growth and proliferation using both biochemical and genetic approaches.

The components of the heat shock response are highly conserved in all major kingdoms, making it one of the most ancient cellular regulatory systems. Yeast is an ideal microbial model system in which to investigate these questions, due to its facile genetics, genomics and ease of manipulation. These studies will impact our understanding of how all eukaryotes, including humans, respond to stress at the molecular level.