Post-translational regulation of the Hsp90 molecular chaperone machinery in cancer
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The evolutionarily conserved molecular chaperone Heat Shock Protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Cancer cells strongly depend on Hsp90 because of their need to cope with constitutive genetic instability and frequent environmental insults, including nutrient deprivation, hypoxia and proteotoxic stress. Emerging clinical data identify Hsp90 inhibition as a promising therapeutic strategy to treat cancer. Cancer cells appear to be particularly sensitive to Hsp90 inhibitors when compared to non-transformed cells, and Hsp90 inhibitors are retained by tumors in vivo far longer than in normal tissues. However, the molecular basis for these phenomena remains undefined.
We use both yeast and mammalian systems to elucidate how post-translational modifications of Hsp90 chaperone machinery work in concert to regulate the chaperone function.