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

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.

Keywords::

• GSH
• c-Myc
• Id2
• N-acetyl-L-cysteine
• histone acetylation
• ChIP assay

Acknowledgements

This work was supported in part by grants from Ministerio de Sanidad (FIS PI05/13332) and Ministerio de Educación y Ciencia (programa Ramón y Cajal) to E.R.G-T, I+D+I, BFU2007-62036 to J.R.V. R.Z and J.S. are a fellows from Ministerio de Educación y Ciencia (programa Juan de la Cierva).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This paper was first published online on Early online on 2 July 2010.