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Updated: Jun 25, 2026
Quantification of three DNA Lesions by Mass Spectrometry and Assessment of Their Levels in Tissues of Mice Exposed to Ambient Fine Particulate Matter
Published on: May 29, 2019
Insight into mechanism of oxidative DNA damage in angiomyolipomas from TSC patients
1Geriatric Research Education and Clinical Center, South Texas Veterans Healthcare System, San Antonio, TX, USA. habib@uthscsa.edu
Background:
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. 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.
Results:
Kidney 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.
Conclusion:
These 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.
Insights
Tuberin deficiency in tuberous sclerosis complex (TSC) kidney tumors leads to increased DNA oxidation due to reduced 8-oxoG-DNA glycosylase (OGG1) levels. This suggests tuberin and OGG1 are key in TSC angiomyolipoma development.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Tuberous sclerosis complex (TSC) arises from mutations in TSC-1 or TSC-2 tumor suppressor genes.
- TSC-2 encodes tuberin, crucial for kidney tumor pathogenesis, including angiomyolipomas and renal cell carcinomas.
- Loss of 8-oxoG-DNA glycosylase (OGG1) function is implicated in kidney tumorigenesis.
Purpose of the Study:
- To investigate the impact of tuberin deficiency on OGG1 levels and DNA oxidation in TSC-associated kidney tumors.
- To assess the phosphorylation status of mTOR downstream targets in TSC kidney tumors.
Main Methods:
- Analysis of tuberin, OGG1, NF-YA, phospho-S6K, and Cyclin D1 expression in TSC patient kidney tumors versus controls.
- Quantification of 8-oxodG (oxidized DNA) levels in tumor and normal kidney tissues.
Main Results:
- TSC kidney tumors showed decreased tuberin and OGG1 expression, alongside increased tuberin phosphorylation.
- Elevated levels of 8-oxodG (4-fold increase) were observed in tumors.
- Increased phosphorylation of S6K and elevated Cyclin D1 expression were associated with tuberin deficiency.
Conclusions:
- Tuberin deficiency in TSC angiomyolipomas promotes mTOR activation and downregulates OGG1, leading to DNA oxidation.
- Tuberin and OGG1 play significant roles in the pathogenesis of angiomyolipoma in TSC patients.