Disease relevance of Hsf1

• Hsf1-/- mice had greater hearing loss than Hsf1+/+ mice, with significant differences in recovery observed at all frequencies tested by 2 weeks after noise [1].
• We further demonstrate that Hsf1 is critical for maintaining cellular integrity after heat stress and that cells from hsf1-/- mice lack the ability to develop thermotolerance [2].
• We hypothesized that Hsf1 plays a role in cell migration, a process necessary for metastases [3].
• Increased synthesis of heat shock proteins (Hsps), mainly regulated by heat shock factor 1 (Hsf1), protects the heart against oxidative stress under pathophysiological conditions such as ischemia/reperfusion [4].
• Several overlapping genomic clones containing the murine HSF-1 gene were isolated from a phage genomic library [5].

High impact information on Hsf1

• This redox-dependent activation of HSF1 by heat and hydrogen peroxide establishes a common mechanism in the stress activation of Hsp gene expression by mammalian HSF1 [6].
• Biochemical and genetic studies have clearly demonstrated critical roles for mammalian heat shock factor 1 (HSF1) in stress-inducible Hsp gene expression, resistance to stress-induced programmed cell death, extra-embryonic development, and other biological functions [6].
• The sensing of both stresses requires two cysteine residues within the HSF1 DNA-binding domain that are engaged in redox-sensitive disulfide bonds [6].
• Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress [6].
• The loop domain of heat shock transcription factor 1 dictates DNA-binding specificity and responses to heat stress [7].

Chemical compound and disease context of Hsf1

• GLN increased unphosphorylated HSF-1 in the nucleus before heat stress [8].

Biological context of Hsf1

• Using Hsf1-/- cells, we show that this factor is responsible for targeting histone H4 acetylation to Hsp70 chromatin [9].
• Using multiple Ag systems, we demonstrated that cross-priming of Ag-specific CD8+ T cells was inefficient when Ag expression was restricted to Hsf1(-/-) non-APCs [10].
• Hsf1-/- mice and their normal littermates (Hsf1+/+) were exposed to a 98-dB, broadband (2-20 kHz) noise for 2 hr, and auditory brainstem response thresholds were measured at three frequencies (4, 12, and 20 kHz) 3 hr, 3 days, and 2 weeks after noise [1].
• Mammalian heat shock factor 1 (Hsf1), which binds conserved sequences on the promoter of the hsp70 gene when cells are exposed to various stress stimuli, utilizes Brg1-SWI/SNF complexes and stimulates transcription in vitro at the level of initiation and elongation [11].
• Thus, the present study demonstrates that Hsf1-dependent transcription of selective Hsps is required for normal renal homeostasis, which protects renal cells against oxidative stress under physiological conditions [4].

Anatomical context of Hsf1

• However, we show here that geldanamycin blocks the development of aggregates of the expanded glutamine androgen receptor (AR112Q) of Kennedy disease in Hsf1(-/-) mouse embryonic fibroblasts where these chaperones are not induced [12].
• We previously demonstrated the presence of Hsf1 in the rodent cochlea and also demonstrated that a heat shock known to precondition the cochlea against noise trauma results in Hsf1 activation in the rodent cochlea [1].
• Increased outer hair cell loss was also observed in Hsf1-/- mice following noise [1].
• We found that the loss of sensory hair cells was more significant in HSF1-null mice compared with that of wild-type mice when mice were subjected to acoustic overexposure [13].
• HSF1 disruption also increased mitochondrial permeability transition pore opening and induced greater mitochondrial membrane potential change (48% increase versus wild type) [4].

Associations of Hsf1 with chemical compounds

• The DNA binding NF-kappaB activity, in particular p50 homodimer activity, was higher in Hsf1(-/-) mice than in wild-type mice after cadmium exposure [14].
• Heat shock protein 25 or inducible heat shock protein 70 activates heat shock factor 1: dephosphorylation on serine 307 through inhibition of ERK1/2 phosphorylation [15].
• Estrogen dependent expression of heat shock transcription factor: implications for uterine synthesis of heat shock proteins [16].
• Indeed, HSF1 deficiency caused a 37% decrease in renal cellular GSH/GSSG ratio, a marker of redox status, and a 40% increase in the rate of mitochondrial superoxide generation in Hsf1 knockout compared with wild-type mice [4].
• Also, HSF1 undergoes phosphorylation in cells exposed to heat or cadmium sulfate but not in cells treated with the amino acid analog L-azetidine-2-carboxylic acid, indicating that phosphorylation of HSF1 is not essential for its activation [17].

Physical interactions of Hsf1

• HSF1 is not activated for DNA-binding at unstressed temperature in Hsf2(-/-) MEFS [18].
• Heat shock-induced dendritic cell maturation is coupled by transient aggregation of ubiquitinated proteins independently of heat shock factor 1 or inducible heat shock protein 70 [19].

Regulatory relationships of Hsf1

• The data indicate that PARP-1 may exert a pathological role in reperfusion injury by functioning as an enhancing factor of AP-1 activation and as a repressing factor of HSF-1 activation and HSP70 expression [20].
• Activation of the heat shock transcription factor (HSF) by heat shock stimulates transcription of the murine hsp70.1 gene (by RNA polymerase II) [21].
• In vivo expression of glycogen synthase kinase 3 alpha or beta thus represses HSF1 through phosphorylation of serine 303 [22].
• The expression of heat shock protein hsp 27 was up-regulated whereas alpha B-crystallin was down-regulated in different areas of HSF1 null mouse brain in comparison to control mice [23].
• When the reporter plasmid was transfected into heat shock factor-1 (HSF-1)-null fibroblasts, the MKP-1 promoter was activated in response to heat shock in a manner similar to that of wild-type fibroblasts with intact HSF-1 [24].

Other interactions of Hsf1

• Among the three known mammalian Hsfs, Hsf1 is recognized as the most effective transactivator of Hsps in response to thermal challenge, but the role of Hsf2 in regulation of genes under normal or increased stress conditions in vivo remains elusive [25].
• All three mammalian HSFs (HSF1, HSF2, HSF4) have also been shown to be required for normal mammalian development [26].
• However, independently of p38 MAP kinase, both stresses strongly activate the transcription factor Hsf1 [9].
• Con sequently, superoxide was generated at a higher rate, and several mitochondrial proteins, including adenine nucleotide translocase 1 (ANT1), were more oxidized by HSF1 deficiency in vivo [27].
• Immune complex kinase assays of heat shocked or SV-pretreated cells indicated that HSF-1 is a potential in vivo substrate for ERK1 phosphorylation [28].

Analytical, diagnostic and therapeutic context of Hsf1

• Gene targeting studies in mice confirm HSF1 as a master regulator required for cell growth, embryonic development, and reproduction [29].
• Sequence analysis of the 5'-untranslated region of HSF-1 suggests that it contains sequences of a recently described Bop1 gene in reverse orientation within its first 331 base pairs (bp) upstream of the translation initiation site [5].
• A gel mobility shift assay revealed that curcumin prolonged the stress-induced activation of the heat shock element-binding (HSE-binding) activity of heat shock transcription factor (Hsf) in the cultured cells [30].
• Western blot analyses indicated that lung protection might be related to the kinetics of HSF1-dependent Hsp70 expression [31].
• Using a cell culture model of migration in a scratch, we found that immortalized MEF cells derived from hsf1-/- animals were deficient in both basal and EGF-induced migration [3].

References