Heat Shock Factor 1 Represses Ras-induced Transcriptional Activation of the c-fos Gene

Abstract

Heat shock factor 1, the critical molecular regulator of the stress response is conserved throughout eukaryotic organisms and activates the transcription of heat shock genes. We now show that heat shock factor 1 inhibits the expression of c-fos, an immediate early gene that controls responses to extracellular stimuli for growth and differentiation. Heat shock factor 1 inhibits the transcription of the c-fos gene and antagonizes the activating effects of the signal transducing protein Ras on the c-fos promoter and on the promoter of another Ras responsive gene uPA. This property was specific for heat shock factor 1; c-fos repression was not seen with the structurally related protein heat shock factor 2. Repression involved different molecular mechanisms compared with those involved in transcriptional activation by heat shock factor 1 and specifically did not require binding to the c-fos promoter. Thus, in addition to its known role as a transcriptional activator of the cellular heat shock response, heat shock factor 1 also antagonizes the expression of Fos, a key component of the ubiquitous AP-1 transcription factor complex and as such could influence multiple aspects of cell regulation.Heat shock results in the activation of a pre-existing transcription factor, heat shock factor 1 (HSF1) 1 through a process that includes trimerization and nuclear translocation (1-3). Activated HSF1 binds to heat shock elements (HSE) in heat shock protein (hsp) gene promoters and induces expression of hsps involved in the assembly, folding, and transport of other proteins and conferring thermotolerence on expressing cells (4 -7). Our recent studies indicate that in addition to being a transcriptional activator, HSF1 functions as a repressor of a number of genes including IL1B (8). This suggests that at elevated temperatures HSF1 possesses both activation and suppression functions, depending on the nature of the target promoter (1,2,8). The function of the heat shock response in mammals is somewhat mysterious considering the tight regulation of body temperature in homeotherms. However, the response may have become adapted to function during fever, the neuroendocrine response to disease that modulates elevation in body temperature (9). Because one function of interleukin 1␤, the product of the IL1B gene and a target for HSF1 repression is the mediation of fever, HSF1 could function as a feedback inhibitor of ILIB during fever (8). We are interested to know whether HSF1 affects other genes involved in cell proliferation, differentiation, and viral infection that might be involved in the heat shock response and the mediation of fever. One such gene is c-fos, an early response gene involved in regulating normal cellular proliferation and differentiation as well as being expressed in many types of tumors (10, 11). c-fos encodes the nuclear Fos protein, which associates with Jun proteins to form a heterodimeric transcription factor with AP-1 site selectivity that is a nuclear target of the Ras signaling pathway and is a participant in t...

Major role of HSP70 as a paracrine inducer of cytokine production in human oxidized LDL treated macrophages

“…4), and pretreatment of the oxLDLsup with blocking antibodies against HSP70 inhibited this increase. The increased IL-1β concentrations was also reduced when using oxLDLsup from macrophages transfected with a plasmid expressing mutated HSF1 (pHSF1mut) that inhibits HSP production [8] (Fig. 4).…”

“…Human macrophages were transiently transfected with a plasmid expressing dominant negative heat shock factor-1 (HSF1) that inhibits the formation of active HSF1 homotrimers (HSF1mut) [8] essentially as previously described [9]. In brief, empty plasmids (25 μg) or HSF1mut plasmids (25 μg) were mixed with 50 μg N- [1-(2,3-dioleoyloxypropyl]-N,N,N,-trimethylammonium methylsulfate (DOTAP) in 500 mL OptiMEM (Roche, Mannheim, Germany) and incubated at room temperature for 20 min before addition to the cultured macrophages for 2.5 h. After 24 h the macrophages were then treated with 50 μg/mL oxLDL or control medium without oxLDL for 24 h at 37°C.…”

Spermatocyte-specific expression of constitutively active heat shock factor 1 induces HSP70i-resistant apoptosis in male germ cells

“…53,54 In addition, HSF1 can also act as a negative regulator of certain non-heat shock genes, including interleukin (IL)-1b or TNFa. [55][56][57] Myers et al 52 had shown that in heat-shocked somatic cells at least two promoters of putative apoptosisrelated genes -TNFRSF member 21 and death domain DNAbinding protein 2 -bound to and were activated by HSF1. Here we have aimed to disclose apoptosis-related genes that are regulated by HSF1 in spermatogenic cells.…”

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

“…In both panels, color-coding goes from red (upregulation) to green (downregulation), with yellow being no change and purple being not identified. Known transcriptional downstream targets of the Ras pathway, such as genes encoding c-Fos, cyclin D1 and p21 Cip1 (Albanese et al, 1995;Chen et al, 1997;Kivinen et al, 1999;Nheu et al, 2004), were upregulated in the transformed cell line and downregulated in reverted cell lines, and have been scored as an internal control of reliability for our results. Other cell cycle-related genes showing the same behavior (i.e.…”