Reduced constitutive 8-oxoguanine-DNA glycosylase expression and impaired induction following oxidative DNA damage in the tuberin deficient Eker rat.

Abstract

The Tsc-2 tumor suppressor gene encodes the protein tuberin, a multi-functional protein with sequence homology to the GTPase activating protein (GAP) for Rap1. Mutations in the Tsc-2 gene are associated with the development of renal tumors. The Eker rat (Tsc-2(EK/+)) bears a mutation in one allele of the Tsc-2 gene, which predisposes these animals to renal cancer. Treatment of wild-type (Tsc-2(+/+)) and mutant (Tsc-2(EK/+)) Eker rats with 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ; 7.5 micro mol/kg. i.v.), a potent redox active and nephrotoxic metabolite of hydroquinone increases the incidence of renal tumors only in animals carrying the mutant Tsc-2(EK/+) allele. We now show that the constitutive expression of 8-oxoguanine-DNA glycosylase (OGG1) in Tsc-2(EK/+) rats is three-fold lower than in wild-type Tsc-2(+/+) rats. Moreover, treatment of wild-type and mutant Eker rats with TGHQ greatly increases 8-oxo-deoxyguanosine (8-oxo-dG) levels within the outer stripe of the outer medulla. Tsc-2(EK/+) rats, with lower constitutive renal OGG1 expression, experience substantially higher levels of 8-oxo-dG than do wild type Tsc-2(+/+) rats. Interestingly, whereas OGG1 expression was rapidly (4 h) induced in Tsc-2(+/+) rats following exposure to TGHQ, it was significantly reduced in Tsc-2(EK/+) rats. The combination of the higher constitutive expression of OGG1 in Tsc-2(+/+) rats, and its rapid induction in response to TGHQ treatment, coupled to the initial decrease in OGG1 expression in Tsc-2(EK/+) rats, results in Tsc-2(EK/+) OGG1 protein levels just 5% of those seen in Tsc-2(+/+) rats 8 h after treatment. Coincidentally, 8-oxo-dG levels in Tsc-2(+/+) rats 8 h after treatment with TGHQ are just 5% of those that occur in Tsc-2(EK/+) rats. The results indicate that the Tsc-2 gene influences constitutive OGG1 expression and the ability of OGG1 to respond to an oxidative stress, consistent with the proposal that Tsc-2 is an acute-phase response gene. In keeping with this view, acute TGHQ-induced cytotoxicity was greater in Tsc-2(EK/+) rats than in Tsc-2(+/+) rats. The mechanism(s) coupling tuberin expression to the regulation of OGG1 are not known and are under investigation.

• Authors: Samy L Habib, Minh N Phan, Sonal K Patel, Donghui Li, Terrence J Monks, Serrine S Lau
• Journal: Carcinogenesis (Carcinogenesis) Vol. 24 Issue 3 Pg. 573-82 (Mar 2003) ISSN: 0143-3334 [Print] England
• PMID: 12663520 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Hydroquinones
• Repressor Proteins
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• 2,3,5-(triglutathion-S-yl)hydroquinone
• N-Glycosyl Hydrolases
• DNA-Formamidopyrimidine Glycosylase
• Glutathione

Topics

• Animals
• Chromatography, High Pressure Liquid
• DNA Damage
• DNA-Formamidopyrimidine Glycosylase
• Electrochemistry
• Fluorescent Antibody Technique
• Glutathione (analogs & derivatives, pharmacology)
• Hydroquinones (pharmacology)
• Kidney (drug effects)
• Male
• N-Glycosyl Hydrolases (metabolism)
• Oxidative Stress
• Rats
• Rats, Mutant Strains
• Repressor Proteins (genetics, physiology)
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins