Induction of REDD1 via AP-1 prevents oxidative stress-mediated injury in hepatocytes.
Free Radic Biol Med
; 124: 221-231, 2018 08 20.
Article
en En
| MEDLINE
| ID: mdl-29909290
Regulated in development and DNA damage responses 1 (REDD1) is an inducible gene in response to various stresses, which functions as a negative regulator of the mammalian target of rapamycin protein kinase in complex 1. In the present study, we identified the role of REDD1 under the oxidative stress-mediated hepatocyte injury and its regulatory mechanism. REDD1 protein was increased in H2O2 or tert-butylhydroperoxide (t-BHP)-treated hepatocytes· H2O2 also elevated REDD1 mRNA levels. This event was inhibited by antioxidants such as diphenyleneiodonium chloride, N-acetyl-L-cysteine, or butylated hydroxy anisole. Interestingly, we found that H2O2-mediated REDD1 induction was transcriptionally regulated by activator protein-1 (AP-1), and that overexpression of c-Jun increased REDD1 protein levels and REDD1 promoter-driven luciferase activity. Deletion of the putative AP-1 binding site in proximal region of the human REDD1 promoter significantly abolished REDD1 transactivation by c-Jun. A NF-E2-related factor 2 activator, tert-butylhydroquinone treatment also elevated REDD1 levels, but it was independent on NF-E2-related factor 2 activation. Furthermore, we observed that REDD1 overexpression attenuated H2O2 or t-BHP-derived reactive oxygen species formation as well as cytotoxicity. Conversely, siRNA against REDD1 aggravated t-BHP-induced reactive oxygen species generation and cell death. In addition, we showed that REDD1 was induced by in vitro or in vivo ischemia/reperfusion model. Our results demonstrate that REDD1 induction by oxidative stress is mainly transcriptionally regulated by AP-1, and protects oxidative stress-mediated hepatocyte injury. These findings suggest REDD1 as a novel molecule that reduced susceptibility to oxidant-induced liver injury.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Daño por Reperfusión
/
Factor de Transcripción AP-1
/
Estrés Oxidativo
/
Sustancias Protectoras
/
Hepatocitos
/
Hígado
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Free Radic Biol Med
Asunto de la revista:
BIOQUIMICA
/
MEDICINA
Año:
2018
Tipo del documento:
Article
Pais de publicación:
Estados Unidos