A ROLE FOR HSP90 IN RETINOID RECEPTOR SIGNAL-TRANSDUCTION

The ubiquitous heat shock protein Hsp90 appears to participate directl y in the function of a broad range of cellular signal transduction com ponents, including steroid hormone receptors; however, an evolutionari ly related subclass of intracellular receptors, exemplified by the ret inoid receptors RAR and RXR, had been inferred from biochemical studie s to function independently of Hsp90. To examine this issue geneticall y, we measured mammalian and avian retinoid receptor activity in a Sac chnromyces cerevisiae strain in which the expression of the yeast Hsp9 0 homologue could be conditionally repressed similar to 20-fold relati ve to wild type. We tested transcriptional activation by RAR or RXR-RA R, from two types of retinoic acid response elements, triggered by thr ee different agonist ligands. In every condition, we found that activa tion was severely compromised under conditions of low Hsp90 expression . We showed that the defect was in signal transduction rather than tra nscription activation per se, and that high affinity hormone binding w as abolished in extracts of cells producing low levels of Hsp90. We su ggest that Hsp90 may function in at least one step of signal transduct ion by all members of the intracellular receptor superfamily.