Antiproliferative prostaglandins activate heat shock transcription factor.

Abstract

Treatment of human K562 erythroleukemia cells with the antiproliferative prostaglandin A1 results in the elevated transcription of two heat shock genes, HSP70 and HSP90. Parallel with increased heat shock gene trnscription is the activation of heat shock transcription factor. Heat shock transcription factor levels are induced within 60 min after prostagandin Al addition to levels similar to that achieved during heat shock. The requirement for protein synthesis for prostaglandin AI activation of heat shock transcription factor suggests that effects on nascent protein synthesis may be involved in the sigaling mechanism. Although it is unclear whether the activation ofa heat shock response by prostalandins is relevant to the biochemical properties of these natural substances, cells pretreated with prostaglandin Al are protected against a subsequent heat shock, indicative of a thermotolerant state.Prostaglandins are a class of naturally occurring cyclic 20-carbon fatty acids that are synthesized from polyunsaturated fatty acid precursors in response to external stimuli such as cell injury and inflammation (1). Prostaglandins function as intracellular hormones involved in the regulation of various physiological and pathological processes of eukaryotes, including cell proliferation and differentiation (2), the immune response (3), inflammation (4), cytoprotection (5, 6), and the febrile response (7).The type A and J prostaglandins, characterized by the presence of a reactive a,4-unsaturated ketone in the cyclopentane ring (cyclopentenone prostaglandins), have antiproliferative activity and cause cultured mammalian cells to arrest in the G1 phase of the cell cycle (8-10). Human erythroleukemia K562 cells, for example, are extremely sensitive to prostaglandin A1 (PGA1), which results in nearly complete cessation of cell growth at doses that do not affect cell viability and do not suppress DNA or RNA synthesis for at least 24 h (11, 12). Treatment with PGA1, PGA2, and PGJ2 results in the elevated synthesis of HSP70, a major heat shock and stress-induced protein (12, 13). Because HSP70 expression is also growth regulated (14, 15), we reasoned that induction of HSP70 by prostaglandins could represent a response to the growth-related effects of this compound. The growth-regulated response of the human HSP70 gene requires cis-acting elements in the basal promoter that are distinct from the distally located heat shock elements on the heat shock gene promoter, which are necessary for heat shock and other forms of stress responsiveness. The cellular response to a wide range of external stress stimuli, including heat shock, heavy metals, amino acid analogues, oxidizing agents, and teratogens (16), involves the activation of heat shock transcription factor (HSF), which binds to the heat shock element (HSE), comprised of multiple adjacent inverted repeats of the pentamer nGAAn (17,18).In this study, we show that the cyclopentenone prostaglandin PGA1 induces in human cells the transcription of classical heat shock genes thr...

The DNA-binding activity of the human heat shock transcription factor is regulated in vivo by hsp70.

“…Inhibiting hsp synthesis with the RNA polymerase II inhibitor DRB (5,6-dichloro-1-D-ribofuranosylbenzimidazole) extends the period of HSF activation in cells given a second heat stress (40). Also, the activation of HSF is reduced in human cells that are preincubated with cycloheximide prior to heat shock treatment (3,4,34). Cycloheximide-treated cells would likely contain an elevated pool of free hsp70 and the cognate hsc72, since nascent polypeptides are a major substrate for the 70-kDa family of stress proteins (6).…”

Inhibition of nuclear factor κB by prostaglandin A1: An effect associated with heat shock transcription factor activation

“…Cyclopentenone PGs are in fact characterized by the ability to selectively induce the expression of specific heat shock genes in a nonstressful situation in mammalian cells (16). Induction is mediated by the activation and translocation to the nucleus of a transregulatory protein, the heat shock transcription factor (HSF), which binds to multiple arrays of heat shock elements (HSEs) located in the promoter of heat shock genes (17). Several HSFs (HSF1-HSF4) have been identified in vertebrate cells (18).…”

Involvement of protein kinase in Δ12‐prostaglandin J2‐induced expression of rat heme oxygenase‐1 gene

“…2A, 2-AP and staurosporine suppressed the ability of A'2-pGJz to stimulate HO-1 mRNA induction, indicating that the inhibition of the A'2-PGJ2-induced HO-I synthesis is due to suppression of the HO-1 gene expression. Recently, an element responsible for 12-O-tetradecanoylphorbol-13-acetate was identified in the mouse HO-1 gene, suggesting involvement of protein kinase C in induction of the mouse HO-1 gene [21]. In RBL-2H3 cells, 12-O-tetradecanoylphorbol-13-acetate could not induce the HO-1 gene expression (data not shown).…”