HSF1 phosphorylation by cyclosporin A confers hyperthermia sensitivity through suppression of HSP expression

Publication date: Available online 3 May 2019Source: Biochimica et Biophysica Acta (BBA) - Gene Regulatory MechanismsAuthor(s): Jingyu Shao, Beibei Han, Pengxiu Cao, Bingwei Zhang, Ming Liu, Danyu Li, Nan Zhou, Qiang Hao, Xianglin Duan, Yanzhong Chang, Akira Nakai, Yumei Fan, Ke TanAbstractHeat shock leads to the activation of heat shock factor 1 (HSF1) and up-regulation of a number of heat shock proteins (HSPs). Cyclosporin A (CsA) is an immunosuppressant that has revolutionized organ transplantation in clinical medicine. However, the roles and regulatory mechanisms of CsA on the HSP expression remain largely unknown. Here, we found that CsA pretreatment prevented the induction of HSPs during heat shock by enhancing the phosphorylation of Ser303 and Ser307 in HSF1 which inhibited HSF1 transcriptional activity. Inhibition of ERK1/2, GSK3β and CK2 ameliorated CsA-induced down-regulation of HSP expressions and up-regulation of HSF1 phosphorylation. CsA impeded HSF1-SSBP1 complex formation, HSF1 nuclear translocation and recruitment to the HSP70 promoter. Due to the low expression of HSPs, CsA treatment clearly caused cell death during proteotoxic stresses. These results indicated that CsA suppressed the induction of HSPs during heat shock through regulation of the phosphorylation and nuclear translocation of HSF1. Our study could provide a conceptual framework for the development of novel strategies for combination therapy utilizing hyperthermia or chemotherapy and CsA treatme...
Source: Biochimica et Biophysica Acta (BBA) Gene Regulatory Mechanisms - Category: Genetics & Stem Cells Source Type: research