INHIBITION OF HSP70 EXPRESSION BY CALCIUM IONOPHORE A23187 IN HUMAN-CELLS - AN EFFECT INDEPENDENT OF THE ACQUISITION OF DNA-BINDING ACTIVITY BY THE HEAT-SHOCK TRANSCRIPTION FACTOR

Heat shock proteins (HSPs) are induced in mammalian cells in a variety of pathophysiological states and have an important role in cytoprotec tion in vitro and in vivo., In this study, we report that the calcium ionophore A23187, a glucose-regulated protein (GRP) inducer, dramatica lly inhibits HSP70 synthesis and HSP70 mRNA transcription after induct ion by heat shock, sodium arsenite, or prostaglandin A(1) treatment in human K562 cells, A23187 does not suppress, and it actually prolongs, the DNA-binding activity of the human heat shock transcription factor (HSF), while it alters HSF1 phosphorylation in heat shock-treated cel ls, To inhibit HSP70 expression, A23187 needs to be present during hea t shock, while treatment before or after heat shock does not affect HS P70 mRNA transcription. The GRP inducer thapsigargin, which specifical ly inhibits the endoplasmic reticulum Ca2+-ATPase, has no effect on he at induced HSP70 synthesis, indicating that A23187 inhibitory activity is not due to depletion of intracellular calcium stores and is indepe ndent of the concomitant induction of GRP genes, Inhibition of HSP70 e xpression is correlated with alterations in HSF1 phosphorylation in he at-shocked cells, but not in sodium arsenite-treated cells, indicating that different mechanisms may be involved in mediating A23187 inhibit ory activity.