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 Hsp90beta generates sensitivity to the Hsp90 inhibitor radicicol.
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, Hsp90alpha and Hsp90beta. Hsp90beta is expressed constitutively to a high level in most tissues and is generally more abundant than Hsp90alpha, whereas Hsp90alpha is stress-inducible and overexpressed in many cancerous cells. Expressed as the sole Hsp90 of yeast, human Hsp90alpha and Hsp90beta are both able to provide essential Hsp90 functions. Activations of certain Hsp90 clients (heat shock transcription factor, v-src) were more efficient with Hsp90alpha, rather than Hsp90beta, 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 Hsp90beta as the sole Hsp90 of yeast rendered cells highly sensitive to the Hsp90 inhibitor radicicol, comparable expression of Hsp90alpha did not. This raises the distinct possibility that, also for mammalian systems, alterations to the Hsp90alpha/Hsp90beta ratio (as with heat shock) might be a significant factor affecting cellular susceptibility to Hsp90 inhibitors.
Department of Molecular Biology and Biotechnology, The University of Sheffield, UK.
Stefan H
SH
Millson
Andrew W
AW
Truman
Attila
A
Rácz
Bin
B
Hu
Barry
B
Panaretou
James
J
Nuttall
Mehdi
M
Mollapour
Csaba
C
Söti
Peter W
PW
Piper
D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D020033:Protein Isoforms; D011994:Recombinant Proteins; D020928:Mitogen-Activated Protein Kinases; C035359:monorden