SHORT-CIRCUITING STRESS PROTEIN EXPRESSION VIA A TYROSINE KINASE INHIBITOR, HERBIMYCIN-A

We set out to identify pharmacological means by which to activate the so-called heat shock or stress response and thereby harness the protec tive effect afforded to the cell by its acquisition of a thermotoleran t phenotype. An earlier report by Murakami et al. (1991, Exp. Cell Res ., 195: 338-344) described the increased expression of the 70 kDa heat shock proteins in human A431 cells exposed to Herbimycin A (HA), a be nzoquinoid ansamycin antibiotic. We show here that treatment of cells with HA results in the increased expression of all of the constitutive ly expressed stress proteins and confers upon the cells a thermotolera nt-like phenotype. increases in the expression of the stress proteins continued for as long as the cells were exposed to the drug and was in dependent of the pre-existing levels of the stress proteins. Unlike he at shock or other metabolic stressors, we did not observe any adverse cellular effects following HA exposure. For example, unlike most agent s/treatments that elicit the stress response HA-treated cells exhibite d no obvious abnormalities with respect to protein maturation, protein insolubility, the integrity of the intermediate filament cytoskeleton , or overall cell viability. in addition, unlike other metabolic stres sors, HA treatment did not result in the translocation of hsp 73 into the nucleus/nucleolus. Finally, for at least rodent cells, HA exposure did not result in any obvious activation of the heat shock transcript ion factor. Based on these findings, we suggest that HA treatment of c ells results in a ''short-circuiting'' of the pathway(s) that normally regulates the expression of the stress proteins. These results are di scussed as they pertain to the potential use of HA in animals as a way to harness the protective effects afforded by the stress response. (C ) 1995 Wiley-Liss, Inc.