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

Samy L. Habib, Minh N. Phan, Sonal K. Patel, Donghui Li, Terrence Monks, Serrine Lau

Research output: Contribution to journalArticle

30 Citations (Scopus)

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-2EK/+) 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-2EK/+) Eker rats with 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ; 7.5 μmol/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-2EK/+ allele. We now show that the constitutive expression of 8-oxoguanine-DNA glycosylase (OGG1) in Tsc-2EK/+ 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-2EK/+ 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-2EK/+ 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-2EK/+ rats, results in Tsc-2EK/+ 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-2EK/+ 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-2EK/+ rats than in Tsc-2+/+ rats. The mechanism(s) coupling tuberin expression to the regulation of OGG1 are not known and are under investigation.

Original languageEnglish (US)
Pages (from-to)573-582
Number of pages10
JournalCarcinogenesis
Volume24
Issue number3
DOIs
StatePublished - Mar 1 2003
Externally publishedYes

Fingerprint

DNA Glycosylases
DNA Damage
Deoxyguanosine
tuberous sclerosis complex 2 protein
8-hydroxyguanine
Kidney
Genes
Alleles
GTPase-Activating Proteins
Amino Acid Sequence Homology
Mutation
Acute-Phase Reaction
Kidney Neoplasms

ASJC Scopus subject areas

  • Cancer Research

Cite this

Reduced constitutive 8-oxoguanine-DNA glycosylase expression and impaired induction following oxidative DNA damage in the tuberin deficient Eker rat. / Habib, Samy L.; Phan, Minh N.; Patel, Sonal K.; Li, Donghui; Monks, Terrence; Lau, Serrine.

In: Carcinogenesis, Vol. 24, No. 3, 01.03.2003, p. 573-582.

Research output: Contribution to journalArticle

@article{db3aa1ef87224e5898616c54ca3bfe75,
title = "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-2EK/+) 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-2EK/+) Eker rats with 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ; 7.5 μmol/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-2EK/+ allele. We now show that the constitutive expression of 8-oxoguanine-DNA glycosylase (OGG1) in Tsc-2EK/+ 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-2EK/+ 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-2EK/+ 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-2EK/+ rats, results in Tsc-2EK/+ 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-2EK/+ 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-2EK/+ rats than in Tsc-2+/+ rats. The mechanism(s) coupling tuberin expression to the regulation of OGG1 are not known and are under investigation.",
author = "Habib, {Samy L.} and Phan, {Minh N.} and Patel, {Sonal K.} and Donghui Li and Terrence Monks and Serrine Lau",
year = "2003",
month = "3",
day = "1",
doi = "10.1093/carcin/24.3.573",
language = "English (US)",
volume = "24",
pages = "573--582",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - Reduced constitutive 8-oxoguanine-DNA glycosylase expression and impaired induction following oxidative DNA damage in the tuberin deficient Eker rat

AU - Habib, Samy L.

AU - Phan, Minh N.

AU - Patel, Sonal K.

AU - Li, Donghui

AU - Monks, Terrence

AU - Lau, Serrine

PY - 2003/3/1

Y1 - 2003/3/1

N2 - 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-2EK/+) 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-2EK/+) Eker rats with 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ; 7.5 μmol/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-2EK/+ allele. We now show that the constitutive expression of 8-oxoguanine-DNA glycosylase (OGG1) in Tsc-2EK/+ 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-2EK/+ 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-2EK/+ 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-2EK/+ rats, results in Tsc-2EK/+ 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-2EK/+ 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-2EK/+ rats than in Tsc-2+/+ rats. The mechanism(s) coupling tuberin expression to the regulation of OGG1 are not known and are under investigation.

AB - 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-2EK/+) 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-2EK/+) Eker rats with 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ; 7.5 μmol/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-2EK/+ allele. We now show that the constitutive expression of 8-oxoguanine-DNA glycosylase (OGG1) in Tsc-2EK/+ 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-2EK/+ 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-2EK/+ 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-2EK/+ rats, results in Tsc-2EK/+ 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-2EK/+ 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-2EK/+ rats than in Tsc-2+/+ rats. The mechanism(s) coupling tuberin expression to the regulation of OGG1 are not known and are under investigation.

UR - http://www.scopus.com/inward/record.url?scp=0037360062&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037360062&partnerID=8YFLogxK

U2 - 10.1093/carcin/24.3.573

DO - 10.1093/carcin/24.3.573

M3 - Article

C2 - 12663520

AN - SCOPUS:0037360062

VL - 24

SP - 573

EP - 582

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 3

ER -