Heat Shock Factor 2 (HSF2) Contributes to Inducible Expression of hsp Genes through Interplay with HSF1

Abstract

The heat shock response is a defense reaction activated by proteotoxic damage induced by physiological or environmental stress. Cells respond to the proteotoxic damage by elevated expression of heat shock proteins (Hsps) that function as molecular chaperones and maintain the vital homeostasis of protein folds. Heat shock factors (HSFs) are the main transcriptional regulators of the stress-induced expression of hsp genes. Mammalian HSF1 was originally identified as the transcriptional regulator of the heat shock response, whereas HSF2 has not been implicated a role in the stress response. Previously, we and others have demonstrated that HSF1 and HSF2 interact through their trimerization domains, but the functional consequence of this interaction remained unclear. We have now demonstrated on chromatin that both HSF1 and HSF2 were able to bind the hsp70 promoter not only in response to heat shock but also during hemin-induced differentiation of K562 erythroleukemia cells. In both cases an intact HSF1 was required in order to reach maximal levels of promoter occupancy, suggesting that HSF1 influences the DNA binding activity of HSF2. The functional consequence of the HSF1-HSF2 interplay was demonstrated by real-time reverse transcription-PCR analyses, which showed that HSF2 was able to modulate the HSF1-mediated expression of major hsp genes. Our results reveal, contrary to the predominant model, that HSF2 indeed participates in the transcriptional regulation of the heat shock response.The heat shock response enables the cell to cope with the deleterious effects of protein-damaging stresses, e.g. heat, heavy metals, and viral and bacterial infections. Characteristic of the heat shock response is a down-regulation of gene transcription and protein synthesis in general, whereas the transcription of a specific subset of genes called the heat shock genes is induced (1, 2). The classical heat shock genes include the hsp genes, but genome-wide analysis has revealed numerous other genes to be activated by heat and other stresses (3). During heat shock, the Hsps 3 function as molecular chaperones that bind to and aid the folding of damaged proteins, thereby preventing protein aggregation under stressful conditions (1, 4, 5). The induction of Hsps is mainly regulated by a family of heat shock transcription factors (HSFs), which bind to the heat shock elements (HSEs) on heat shock genes and other target genes (6 -9).Four HSFs (HSF1-4) exist in vertebrates. HSF1 and HSF2 are the most studied factors because of their co-expression in most tissues and cell lines (9). HSF3 has been found only in avian species, and HSF4 is the most recently identified member in mammals and expressed predominantly in lens and brain (10 -15). Mammalian HSF1 corresponds to the single HSF in yeast, nematode, and fruit fly (16 -19) and is considered the bona fide stress-activated transcription factor. Mice lacking HSF1 and fibroblasts derived from these animals are sensitive to stress and do not develop thermotolerance or display induction of Hsps upo...

Promoter ChIP-chip analysis in mouse testis reveals Y chromosome occupancy by HSF2

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Hyperfluidization-coupled membrane microdomain reorganization is linked to activation of the heat shock response in a murine melanoma cell line

“…The ChIP protocol is described by Ö stling et al (40). Sonicated chromatin was immunoprecipitated with HSF1 (SPA-901; Stressgen, Victoria, Canada), acetylated histone H4 (06-866; Upstate Biotechnologies, Lake Placid, NY) antibodies or normal rabbit serum (NS; Jackson ImmunoResearch Laboratory, Bar Harbor, ME).…”

Induction of Heat Shock Proteins by Hyperthermia and Noise Overstimulation in Hsf1 −/− Mice

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