Abstract
BackgroundThe tuberous 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, both angiomyolipomas and renal cell carcinomas. Loss of heterozygosity at the 8-oxoG-DNA glycosylase (OGG1) allele is found in human kidney clear cell carcinoma identifying loss of OGG1 function as a possible contributor to tumorigenesis in the kidney. Tuberin regulates OGG1 through the transcription factor NF-YA in cultured cells. The purpose of this study is to determine the effect of tuberin-deficiency on OGG1 protein and mRNA levels as well as on 8-oxodG levels in kidney tumors from patients with TSC. In addition we evaluated the phophorylation level of downstream targets of mTOR, phospho-S70K, in kidney tumor tissue from TSC patients.ResultsKidney angiomyolipoma tissue from TSC patients expresses significant levels of phopho-tuberin and low levels of tuberin compared to control kidney tissue. The increase in tuberin phosphorylation and the decrease tuberin expression are associated with decrease in OGG1 protein and mRNA levels in tumor samples compared to normal kidney samples. The decrease OGG1 expression is also associated with significant decrease in the transcription factor, NF-YA, expression in tumor samples compared to normal tissues. In addition, the levels of 8-oxodG are 4-fold higher in tumors compared to control samples. The significant increase of phospho-tuberin expression is associated with increase phosphorylation of S6K in tumor samples compared to controls. Cyclin D1 expression is also 3-fold higher in increase in the tumor tissues compared to normal kidney tissues.ConclusionThese data indicate that tuberin deficiency in angiomyolipoma enhances mTOR activation by phosphorylation of S6K and downregulation of protein and mRNA expression of OGG1 resulted in accumulation of oxidized DNA in patients with TSC. These data suggest that tuberin and OGG1 are important proteins in the pathogenesis of angiomyolipoma in TSC patients.
Highlights
The tuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, TSC-1 or TSC-2
Tuberin phosphorylation is increased and is associated with decreased tuberin and 8-oxoG-DNA glycosylase (OGG1) expression in kidney angiomyolipoma tissue To determine the relevance of our findings in cell culture [23] and rodents [21,22] to humans, phopho-tuberin, total tuberin and OGG1 expression was assessed in tissue homogenates of control kidney tissue and kidney tumors from patients with tuberous sclerosis
In addition decrease tuberin expression is associated with significant decrease in the mRNA and protein levels of OGG1 in tumor tissue compared to control tissue (Figure 2A and Figure 2B)
Summary
The tuberous 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, both angiomyolipomas and renal cell carcinomas. The purpose of this study is to determine the effect of tuberin-deficiency on OGG1 protein and mRNA levels as well as on 8-oxodG levels in kidney tumors from patients with TSC. Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder associated with tumors in many organs, angiomyolipoma in the kidneys and renal cell carcinoma (RCC). Molecular Cancer 2009, 8:13 http://www.molecular-cancer.com/content/8/1/13 associated hamartomas and renal cell carcinoma (RCC) as well as in sporadic tumors of non-TSC patients [2]. The TSC2 gene product (tuberin) is a tumor suppressor protein whose absence or inactivation is associated with several defects such as abnormal cellular migration, proliferation, and differentiation [6,7]. These phosphorylations by Akt disrupt the TSC1-TSC2 complex and disturb the subcellular localization of TSC1 and TSC2 [11]
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