Diverse effects of stat1 on the regulation of hsp90α gene under heat shock

Stat1 has been known as a regulator of gene expression and a mediator of IFN gamma signaling in mammalian cells, while its effect in a heat shock response remains unclear. We used RNAi knockdown, point mutations, ChIP and promoter activity assays to study the effect of Stat 1 on the heat-shock induction of the hsp90 alpha gene under heat shock conditions. We found that Stat 1 regulates the heat shock induction of its target genes, the hsp90 alpha: gene in a heat shock response while the constitutive activity of the gene remains unaffected. The result of Stat 1 in complex with Stat3 and HSF 1 that bound at the GAS to lead a moderate heat shock induction was designated as an "intrinsic" induction of the hsp90 alpha gene. Additionally a reduced or an elevated level of heat shock induction was also controlled by the Stat 1 on hsp90 alpha. These diverse effects on the hsp9 alpha gene were a "reduced" induction with overexpressed Stat1 elicited by transfection of wild-type Stat1 or IFN gamma treatment, bound at the GAS as homodimer; and an "enhanced" heat shock induction with a mutation-mediated prohibition of Stat1/GAS binding. In conclusion, the status and efficacy of Stat1 bound at the GAS of its target gene are pivotal in determining the impact of Stat1 under heat shock. The results provided the first evidence on the tumor suppressor Stat1 that it could play diverse roles on its target genes under heat shock that also shed lights on patients with fever or under thermotherapy. J. Cell. Biochem. 102: 1059-1 066,2007. (C) 2007 Wiley-Liss, Inc.