Signal transducer and activator of transcription-1 and heat shock factor-1 interact and activate the transcription of the Hsp-70 and Hsp-90β gene promoters

Abstract

We have previously demonstrated that interleukin-6 (IL-6) increases the levels of the heat shock protein 90 (Hsp-90) and activates the Hsp-90β promoter via the IL6-activated transcription factors NF-IL6 and signal transducer and activator of transcription-3 (STAT-3). Here, we show that interferon-γ (IFN-γ) treatment increases the levels of Hsp-70 and Hsp-90 and also enhances the activity of the Hsp-70 and Hsp-90β promoters with these effects being dependent on activation of the STAT-1 transcription factor by IFN-γ. These effects were not seen in a STAT-1-deficient cell line, indicating that IFN-γ modulates Hsp induction via a STAT-1-dependent pathway. The effect of IFN-γ/STAT-1 was mediated via a short region of the Hsp-70/Hsp-90 promoters, which also mediates the effects of NF-IL6 and STAT- 3 and can bind STAT-1. This region also contains a binding site for the stress-activated transcription factor HSF-1. We show that STAT-1 and HSF-1 interact with one another via a protein-protein interaction and produce a strong activation of transcription, which is in contrast to our previous finding that STAT-3 and HSF-1 antagonize one another. To our knowledge this is the first report of HSF-1 interacting directly via a protein-protein interaction with another transcription factor. Such proteinprotein interactions and the binding of a number of different stress and cytokine- activated transcription factors to a short region of the Hsp-90 and Hsp-70 gene promoters are likely to play a very important role in Hsp gene activation by non-stressful stimuli and the integration of these responses with the stress response of these genes.