Tuberin haploinsufficiency is associated with the loss of OGG1 in rat kidney tumors

Samy L Habib,Simona Simone,Hanna E Abboud,Jeff J Barnes

doi:10.1186/1476-4598-7-10

Abstract

BackgroundTuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, TSC-1 or TSC-2. TSC-2 gene encodes tuberin, a protein involved in the pathogenesis of kidney tumors. Loss of heterozygosity (LOH) at the TSC2 locus has been detected in TSC-associated renal cell carcinoma (RCC) and in RCC in the Eker rat. Tuberin downregulates the DNA repair enzyme 8-oxoguanine DNA-glycosylase (OGG1) with important functional consequences, compromising the ability of cells to repair damaged DNA resulting in the accumulation of the mutagenic oxidized DNA, 8-oxo-dG. Loss of function mutations of OGG1 also occurs in human kidney clear cell carcinoma and may contribute to tumorgenesis. We investigated the distribution of protein expression and the activity of OGG1 and 8-oxo-dG and correlated it with the expression of tuberin in kidneys of wild type and Eker rats and tumor from Eker rat.ResultsTuberin expression, OGG1 protein expression and activity were higher in kidney cortex than in medulla or papilla in both wild type and Eker rats. On the other hand, 8-oxo-dG levels were highest in the medulla, which expressed the lowest levels of OGG1. The basal levels of 8-oxo-dG were also higher in both cortex and medulla of Eker rats compared to wild type rats.In kidney tumors from Eker rats, the loss of the second TSC2 allele is associated with loss of OGG1 expression. Immunostaining of kidney tissue shows localization of tuberin and OGG1 mainly in the cortex.ConclusionThese results demonstrate that OGG1 localizes with tuberin preferentially in kidney cortex. Loss of tuberin is accompanied by the loss of OGG1 contributing to tumorgenesis. In addition, the predominant expression of OGG1 in the cortex and its decreased expression and activity in the Eker rat may account for the predominant cortical localization of renal cell carcinoma.

Highlights

Tuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, TSC-1 or TSC-2
Decrease in 8-oxoG-DNA glycosylase (OGG1) activity is associated with increases 8oxodG in Eker rat To determine if the decreases in OGG1 protein expression correlates with the enzymatic activity, OGG1 activity was compared in kidneys from wild type or Eker rats
OGG1 activity was significantly lower in kidney cortex and medulla of Eker rats compared to wild type rats (Fig. 2B)

Summary

Introduction

Tuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, TSC-1 or TSC-2. Tuberin downregulates the DNA repair enzyme 8-oxoguanine DNA-glycosylase (OGG1) with important functional consequences, compromising the ability of cells to repair damaged DNA resulting in the accumulation of the mutagenic oxidized DNA, 8-oxo-dG. Loss of function mutations of OGG1 occurs in human kidney clear cell carcinoma and may contribute to tumorgenesis. (background) levels of these modifications and create a mutator phenotype that predisposes to malignant transformation [1,2,3] Many of these mutations occur as a result of irreparable or incompletely repaired genomic DNA, which is constantly subject to assault from intrinsic and environmental insults. Oxidative damage-induced mutations activate oncogenes or inactivate tumor suppressor genes, altering cell growth control. The gene encoding the DNA repair enzyme that recognizes and excises 8-oxodG is 8oxoG-DNA glycosylase (OGG1) [10]. Loss of heterozygosity at the OGG1 allele, located on chromosome 3p25, was found in 85% of 99 human kidney clear cell carcinoma samples, identifying the loss of OGG1 function as a possible consequence of multistep carcinogenesis in the kidney [15]

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