Glutamine-mediated dual regulation of heat shock transcription factor-1 activation and expression.
J Biol Chem
; 287(48): 40400-13, 2012 Nov 23.
Article
em En
| MEDLINE
| ID: mdl-23055521
ABSTRACT
BACKGROUND:
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.RESULTS:
Glutamine increases Hsf1 gene transcription in a C/EBPß-dependent manner and up-regulates HSF1 activity.CONCLUSION:
Glutamine is an activator for both HSF1 expression and transactivation.SIGNIFICANCE:
Glutamine-induced HSF1 expression provides a novel mechanistic frame for HSF1-Hsp axis regulation. Heat shock transcription 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 the transactivation activity of HSF1. How HSF1 expression is regulated remains unknown. Herein 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. More 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 the HSF1 response to Gln. C/EBPß was further shown to bind to this 82-bp sequence both in vitro and in vivo. Gln availability strikingly altered the ratio of C/EBPß inhibitory and active isoforms, i.e. liver-enriched inhibitory protein and liver-enriched activating protein. Liver-enriched inhibitory protein and liver-enriched activating protein were further shown to be an independent repressor and activator, respectively, for Hsf1 gene transcription, and the relative abundance of these two C/EBPß isoforms was demonstrated to determine Hsf1 transcription. We show for the first time that Gln not only enhances the transactivation of HSF1 but also induces Hsf1 expression by activating its transcription in a C/EBPß-dependent manner.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Ativação Transcricional
/
Regulação da Expressão Gênica
/
Proteínas de Ligação a DNA
/
Glutamina
Limite:
Animals
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos