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 cytoprotection in vitro and in vivo. In this study, we report that the calcium ionophore A23187, a glucose-regulated protein (GRP) inducer, dramatically inhibits HSP70 synthesis and HSP70 mRNA transcription after induction by heat shock, sodium arsenite, or prostaglandin A1 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 cells. To inhibit HSP70 expression, A23187 needs to be present during heat shock, while treatment before or after heat shock does not affect HSP70 mRNA transcription. The GRP inducer thapsigargin, which specifically inhibits the endoplasmic reticulum Ca2+-ATPase, has no effect on heat-induced HSP70 synthesis, indicating that A23187 inhibitory activity is not due to depletion of intracellular calcium stores and is independent of the concomitant induction of GRP genes. Inhibition of HSP70 expression is correlated with alterations in HSF1 phosphorylation in heat-shocked cells, but not in sodium arsenite-treated cells, indicating that different mechanisms may be involved in mediating A23187 inhibitory activity.
Elia
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Institute of Experimental Medicine, Consiglio Nazionale delle Ricerche, Viale K. Marx, 15/43, 00137 Rome, Italy.
De Marco
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Rossi
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Santoro
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D000001:Calcimycin / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D000076249:Heat Shock Transcription Factors; D006358:Hot Temperature; D006801:Humans; D007476:Ionophores / Q000494:pharmacology*; D004915:Leukemia, Erythroblastic, Acute; D008565:Membrane Proteins / Q000096:biosynthesis; D008715:Methionine / Q000378:metabolism; D018832:Molecular Chaperones / Q000096:biosynthesis; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D007476:Ionophores; D008565:Membrane Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D013729:Terpenes; D014157:Transcription Factors; C018551:glucose-regulated proteins; D000001:Calcimycin; D019284:Thapsigargin; D008715:Methionine; D000252:Calcium-Transporting ATPases