Transcriptional regulation of the heat shock protein genes by STAT family transcription factors.

We have previously demonstrated that interleukin-6 (IL-6) increases the levels of the heat shock protein 90 (Hsp90) and activates the Hsp90beta promoter via the IL-6-activated transcription factors NF-IL6 and STAT-3. In addition, interferon-gamma (IFN-gamma) treatment increases the levels of Hsp70 and Hsp90 and also enhances the activity of the Hsp70 and Hsp90beta promoters with these effects being dependent on activation of the STAT-1 transcription factor by IFN-gamma. The effect of IL-6/STAT-3 and IFN-gamma/STAT-1 was mediated via a short region of the Hsp70/Hsp90 promoters, which also mediates the effects of NF-IL6. This region also contains a binding site for the stress-activated transcription factor HSF-1. Furthermore, STAT-1 and HSF-1 interact with one another via a protein-protein interaction and produce a strong activation of transcription. In contrast, STAT-3 and HSF-1 antagonize one another and reduce the activation of both the Hsp70 and Hsp90 promoters. Thus, STAT-1 or STAT-3 activation alone or together results in the activation of Hsp promoters. However, STAT-1 or STAT-3 interact differently with HSF-1 to regulate Hsp promoter activity. These results indicate that STATs are able to moduate the Hsp70 and Hsp90 gene promoters and that these transcription factors are likely to play a very important role in Hsp gene activation by nonstressful stimuli and the integration of these responses with the stress response of these genes.