Abstract
Heat shock factor‐1 (HSF1) is the master regulator for cytoprotective heat shock protein (Hsp) expression. It is widely thought that HSF1 expression is non‐inducible and thus the key control point of HSP expression is regulation of HSF1's transactivation activity. How HSF1 expression is regulated remains unknown. Herein, we demonstrate that glutamine (Gln) enhanced Hsp expression both in rat colonic epithelium in vivo and in cultured non‐transformed colonic YAMC cells. This was associated with upregulated HSF1's transactivation activity via increased HSF1 trimerization, nuclear localization and DNA binding. Intriguingly, Gln enhanced HSF1 protein and mRNA expression and Hsf1 gene promoter activity. Within the −281/−200 region of the Hsf1 promoter, deletion of the putative CCAAT enhancer binding protein (C/EBP) binding site abolished Gln's HSF1 response. Gln availability strikingly altered the ratio of C/EBPβ inhibitory and active isoforms, i.e., liver‐enriched inhibitory protein (LIP) and liver‐enriched activating protein (LAP). LIP and LAP were further shown to be independent repressor and activator respectively for Hsf1 gene transcription and the relative abundance of these two C/EBPβ isoforms was demonstrated to determine Hsf1 transcription. We show for the first time that Gln not only enhances HSF1's transactivation, but also induces Hsf1 gene transcription in a C/EBPβ‐dependent manner.
Highlights
Regulation of transcriptional activity of heat shock factor-1 (HSF1) is widely thought to be the main point of control for heat shock protein (Hsp) expression
We report for the first time that Gln enhances Heat shock transcription factor-1 (HSF1) activation and intriguingly up-regulates actual Hsf1 gene expression per se. We demonstrate that this up-regulation of Hsf1 gene expression occurs at the transcriptional level, and the amino acid-responsive CCAAT enhancer-binding protein (C/EBP)  [25,26,27,28] is essential for this Gln-mediated HSF1 response
To investigate whether Gln can up-regulate Hsp gene promoter activity and lead to transcriptional activation of the Hsp genes, we studied the Hsp70 promoter-driven reporter gene expression pattern in cells exposed to Gln
Summary
Regulation of transcriptional activity of heat shock factor-1 (HSF1) is widely thought to be the main point of control for heat shock protein (Hsp) expression. We demonstrate that glutamine (Gln), a preferred fuel substrate for the gut, enhanced Hsp expression both in rat colonic epithelium in vivo and in cultured non-transformed young adult mouse colonic epithelial cells This was associated with up-regulation of the transactivation activity of HSF1 via increased HSF1 trimerization, nuclear localization, DNA binding, and relative abundance of activating phosphorylation at Ser-230 of HSF1. How HSF1 proceeds through a multistep pathway involving a monomer-to-trimer transition, nuclear accumulation, acquisition of DNA binding ability, and extensive posttranslational modifications has been a primary focus of a large body of research directed at understanding the regulation of Hsp expression [2, 3, 7,8,9] Contrary to this notion, new evidence has recently emerged suggesting that HSF1 expression may not remain constant and can be induced (10 –14). Hyperthermia [11, 14], laser therapy [13], and hemorrhagic shock [10] have been reported to up-regulate HSF1 mRNA expression in multiple tissues and cell types, suggesting that regulation of HSF1 expression may occur at a pretransla-
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