Molecular mechanisms of Id2 down-regulation in rat liver after acetaminophen overdose. Protection by N-acetyl-L-cysteine.
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.
Penella
Estela
E
Departamento de Bioquímica y Biología Molecular, Fundación Investigación Hospital Clínico Valencia / INCLIVA, Universidad de Valencia, Spain.
Sandoval
Juan
J
Zaragozá
Rosa
R
García
Concha
C
Viña
Juan R
JR
Torres
Luis
L
García-Trevijano
Elena R
ER
D000082:Acetaminophen / Q000494:pharmacology / Q000506:poisoning*; D000111:Acetylcysteine / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology / Q000506:poisoning; D000818:Animals; D019610:Cytoprotection / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D062787:Drug Overdose; D005786:Gene Expression Regulation / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism / Q000502:physiology; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D018712:Analgesics, Non-Narcotic; C497451:Id2 protein, rat; D051797:Inhibitor of Differentiation Protein 2; D000082:Acetaminophen; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione; D000111:Acetylcysteine