Molecular mechanisms of Id2 down-regulation in rat liver after acetaminophen overdose. Protection by N-acetyl-L-cysteine
| Autor: | Penella E, Sandoval J, Zaragozá R, García C, Viña JR, Torres L, García-Trevijano ER |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | Free radical research r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe instname |
| ISSN: | 1071-5762 |
| Popis: | Id2 is a pleiotropic protein whose function depends on its expression levels. Id2-deficient cells show increased cell death. This study explored the molecular mechanisms for the modulation of Id2 expression elicited by GSH and oxidative stress in the liver of acetaminophen (APAP)-intoxicated rats. APAP-overdose induced GSH depletion, Id2 promoter hypoacetylation, RNApol-II released and, therefore, Id2 down-regulation. Id2 expression depends on c-Myc binding to its promoter. APAP-overdose decreased c-Myc content and binding to Id2 promoter. Reduction of c-Myc was not accompanied by decreased c-myc mRNA, suggesting a mechanism dependent on protein stability. Administration of N-acetyl-cysteine prior to APAP-overload prevented GSH depletion and c-Myc degradation. Consistently, c-Myc was recruited to Id2 promoter, histone-H3 was hyperacetylated, RNApol II was bound to Id2 coding region and Id2 repression prevented. The results suggest a novel transcriptional-dependent mechanism of Id2 regulation by GSH and oxidative stress induced by APAP-overdose through the indirect modulation of the proteasome pathway. |
| Databáze: | OpenAIRE |
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