Heat shock factor (HSF) 1 is the major heat shock transcription factor that regulates stress-inducible synthesis of heat shock proteins and is also essential in protection against endotoxic shock. Following our previous study, which demonstrated the transcriptional repression of the IL-1␤ gene by HSF1 (Cahill, C. M., Waterman, W. R., Xie, Y., Auron, P. E., and Calderwood, S. K.

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...