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 J.
AU - Lau, Serrine S.
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.
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U2 - 10.1093/carcin/24.3.573
DO - 10.1093/carcin/24.3.573
M3 - Review article
C2 - 12663520
AN - SCOPUS:0037360062
SN - 0143-3334
VL - 24
SP - 573
EP - 582
JO - Carcinogenesis
JF - Carcinogenesis
IS - 3
ER -