Disease relevance of HSF2

• HSF1 is activated by heat shock and other forms of stress, whereas HSF2 is activated during hemin-induced differentiation of human K562 erythroleukemia cells, suggesting a role for HSF2 in regulating heat shock gene expression under nonstress conditions such as differentiation and development [1].
• In contrast, HSF2 is not activated by heat stress and has been speculated to have developmental functions [2].
• Furthermore, while quercetin treatment inhibited HSF2 expression, it only slightly affected HSF1 expression in breast cancer cells [3].
• HSF1 transcriptional activity has been discussed in neuronal cells, concentrating on the regulation and activity of HSF1 and HSF2 and their role in HSP expression, during neurodegenerative diseases and as mediators of cell survival [4].

High impact information on HSF2

• Here, we show that point mutations in either of two amino-terminal zippers or in the carboxy-terminal zipper disrupt normal localization of HSF2 and cause it to be constitutively nuclear [5].
• Expression of HSP-70, HSF1, and HSF2 genes and protein were determined [6].
• Moreover, hHSF1 and hHSF2 exhibit selectivity for transcriptional activation of two distinct yeast heat shock responsive genes, which correlate with previously established mammalian HSF DNA binding preferences in vitro [7].
• Hence, SUMO modification of the HSF2 loop contributes to HSF-specific regulation of DNA binding and broadens the concept of sumoylation in the negative regulation of gene expression [8].
• We demonstrate that enhanced HSF2 expression and the acquisition of HSF2 DNA binding activity are strictly specific for erythroid characteristics of K562 cells [9].

Biological context of HSF2

• We show here that a chimeric polypeptide of HSF2 and GAL4 DNA binding domain (GAL4-BD-HSF2) was unable to induce a GAL4 binding site-containing luciferase reporter gene in response to hemin and that exogenously overproduced HSF2 also failed to increase expression of a heat shock element-containing reporter [10].
• In addition, HSF2 regulation involves differential activity of two isoforms, HSF2A and HSF2B, which arise from alternative splicing of a common hsf2 gene [11].
• Although heat shock factor 2 (HSF2) binds to heat shock element (HSE) constitutively during differentiation, development and spermatogenesis, little is known about the nature and mechanism of transcriptional control of heat shock genes by HSF2 [12].
• This is the first demonstration that HSF2 can be activated by KCl and is involved in the upregulation of alphaB-crystallin gene expression in glial cells [13].
• Recent reports have suggested that both HSF1 and HSF2 are affected during down-regulation of ubiquitin-proteasome pathway (Y. Kawazoe et al., Eur. J. Biochem. 255:356-362, 1998; A. Mathew et al., Mol. Cell. Biol. 18:5091-5098, 1998; D. Kim et al., Biochem. Biophys. Res. Commun. 254:264-268, 1999) [14].

Anatomical context of HSF2

• Our results reveal that the inactive, non-DNA-binding forms of HSF2 and HSF1 exist primarily in the cytoplasm of untreated K562 cells as a dimer and monomer, respectively [1].
• Using these tools, we have shown that human HeLa cells constitutively synthesize HSF1, but we were unable to detect HSF2 [15].
• HSF2BP may therefore be involved in modulating HSF2 activation in testis [12].
• In contrast, strong Hsp70 induction occurred in motor neurons with expression of a constitutively active form of heat shock transcription factor (HSF)-1 or when proteasome activity was sufficiently inhibited to induce accumulation of an alternative transcription factor HSF2 [16].
• These results demonstrate that ROS stimulates RANKL expression via ERKs and PKA-CREB pathway in mouse osteoblasts and via ERKs and HSF2 in human MG63 cells [17].

Associations of HSF2 with chemical compounds

• Our results identify lysine 82 as the major site of SUMO-1 modification in HSF2, which is located in a "wing" within the DNA-binding domain of this protein [18].

Physical interactions of HSF2

• In this study, we demonstrate that the less-well characterized HSF2 interacts physically with HSF1 and is a novel stress-responsive component of the stress granules [19].
• In addition, HSF2 is not capable of binding to NF-IL6 [20].
• Sumo-1 modification regulates the DNA binding activity of heat shock transcription factor 2, a promyelocytic leukemia nuclear body associated transcription factor [18].
• Acquisition of heat shock factor 2 (HSF2) DNA binding activity is accompanied by induced transcription of heat shock genes in hemin-treated K562 cells undergoing erythroid differentiation [21].

Regulatory relationships of HSF2

• Based on analysis of our deletion mutants, HSF2 influences to the localization of HSF1 in stress granules [19].
• HSF2 has been thought to be responsible for accumulation of HSP70 during hemin-induced differentiation of human K562 erythroleukemia cells because of accompanying acquisition of HSF2 DNA binding activity [10].
• Overexpression of HSF2-beta inhibits hemin-induced heat shock gene expression and erythroid differentiation in K562 cells [21].
• In this study, we report that thioredoxin (TRX) expression is induced in K562 cells in response to hemin in an HSF2-dependent manner [22].
• Together, the results in this work suggest a mechanism in which MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes in the vicinity of HSF2 [23].

Other interactions of HSF2

• We report here that hemin activates the DNA-binding activity of HSF2, whereas heat shock induces predominantly the DNA-binding activity of a distinct factor, HSF1 [24].
• Interestingly, SUMO-1 modification of HSF2 results in conversion of this factor to the active DNA binding form [18].
• These results indicate that HSF1, rather than HSF2, primarily mediates the hemin-induced transcription of the hsp70 gene [10].
• Staining with anti-promyelocytic leukemia antibodies indicates that these HSF2-containing nuclear granules are PML bodies [18].
• These data suggest the possibility that p62 is involved in the activation or regulation of HSF2 [25].

Analytical, diagnostic and therapeutic context of HSF2

• Electron microscopy reveals that HSF2 will bring together distant DNA sites to create a loop [26].
• Western blot analysis indicated that HSF1 but not HSF2 protein levels were reduced in aged donor samples [27].
• In addition to real-time PCR and immunoblotting, gel mobility shift assays, coupled with specific antibodies and HSE probes, derived from three different heat shock promoters, establish that there is no HSF1 or HSF2 binding activity in the postnatal lens nuclear extracts [28].
• We demonstrated physical interaction between HSF2 and p62 both by a glutathione S-transferase (GST) pull-down assay in vitro and by a two-hybrid assay in K562 cells [25].
• Western blotting, immunohistochemistry and RT-PCR showed that mRNA and protein of HSF1 and HSF2 were present in the rat retina and predominantly expressed in RGC layer cells [29].

References