Molecular mechanisms of Id2 down-regulation in rat liver after acetaminophen overdose. Protection by N-acetyl-L-cysteine

• Published in: Free radical research 2010-09, Vol.44 (9), p.1044-1053
• Main Authors: Penella, Estela, Sandoval, Juan, Zaragozá, Rosa, García, Concha, Viña, Juan R., Torres, Luis, García-Trevijano, Elena R.
• Format: Article
• Language: English
• Subjects: Acetaminophen - pharmacology; Acetaminophen - poisoning; Acetylcysteine - pharmacology; Analgesics, Non-Narcotic - pharmacology; Analgesics, Non-Narcotic - poisoning; Animals; c-Myc; ChIP assay; Cytoprotection - drug effects; Down-Regulation - drug effects; Down-Regulation - genetics; Drug Overdose; Gene Expression Regulation - drug effects; Genes, myc - drug effects; Glutathione - metabolism; Glutathione - physiology; GSH; histone acetylation; Id2; Inhibitor of Differentiation Protein 2 - genetics; Inhibitor of Differentiation Protein 2 - metabolism; Liver - drug effects; Liver - metabolism; Male; N-acetyl-L-cysteine; Oxidative Stress - drug effects; Oxidative Stress - genetics; Oxidative Stress - physiology; Proteasome Endopeptidase Complex - metabolism; Proteasome Endopeptidase Complex - physiology; Rats; Rats, Wistar; Signal Transduction - drug effects; Signal Transduction - genetics
• ISSN: 1071-5762; 1029-2470
• DOI: 10.3109/10715762.2010.498825

Abstract 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.