Investigators

Summary

Our work focuses on understanding: (1) how misfolded proteins are recognized and destroyed in normal and tumor cells, (2) how molecular chaperones mediate protein quality control “decisions”, (3) how protein quality control pathways can be targeted in disease models, and (4) how cellular stress responses (such as the Unfolded Protein Response, UPR) affect protein biogenesis and homeostasis, especially in cancer. The pursuit of these goals has employed biochemical, cell biological, and genetic tools using a range of models, including yeast, cell culture, and rodents. Our early work contributed to the discovery of the ER associated degradation (ERAD) pathway, which we named, and ongoing studies are deciphering the mechanisms underlying the ERAD pathway in yeast, mammalian cell culture, and rodent models, and its relationship to cellular stress responses. The importance of ERAD is underscored by the fact that >70 human diseases—including several cancers—are associated with this pathway. In parallel, new classes of small molecule modulators of chaperones and the ubiquitin-proteasome pathway have also been isolated, which we have used to probe the relationship between stress responses, protein homeostasis (“proteostasis”), and tumorigenesis. Ongoing work has capitalized on several of our tools and areas of expertise, including (1) an analysis of protein degradation pathways and the ubiquitin-proteasome system in breast and ovarian cancer, (2) the use of small molecules and drugs to target cancer vulnerabilities, and (3) measurements of cellular stress pathways in breast and ovarian cancer.