Expressed as the sole Hsp90 of yeast, the alpha and beta isoforms of human Hsp90 differ with regard to their capacities for activation of certain client proteins, whereas only Hsp90 beta generates sensitivity to the Hsp90 inhibitor radicicol

摘要

Heat shock protein 90 (Hsp90) is a molecular chaperone required for the activity of many of the most important regulatory proteins of eukaryotic cells (the Hsp90 'clients'). Vertebrates have two isoforms of cytosolic Hsp90, Hsp90 alpha and Hsp90 beta. Hsp90 beta is expressed constitutively to a high level in most tissues and is generally more abundant than Hsp90 alpha, whereas Hsp90 alpha is stress-inducible and overexpressed in many cancerous cells. Expressed as the sole Hsp90 of yeast, human Hsp90 alpha and Hsp90 beta are both able to provide essential Hsp90 functions. Activations of certain Hsp90 clients (heat shock transcription factor, v-src) were more efficient with Hsp90 alpha, rather than Hsp90 beta, present in the yeast. In contrast, activation of certain other clients (glucocorticoid receptor; extracellular signal-regulated kinase-5 mitogen-activated protein kinase) was less affected by the human Hsp90 isoform present in these cells. Remarkably, whereas expression of Hsp90 beta as the sole Hsp90 of yeast rendered cells highly sensitive to the Hsp90 inhibitor radicicol, comparable expression of Hsp90 alpha did not. This raises the distinct possibility that, also for mammalian systems, alterations to the Hsp90 alpha/Hsp90 beta ratio (as with heat shock) might be a significant factor affecting cellular susceptibility to Hsp90 inhibitors