Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, TSC-1 or TSC-2. The TSC-2 gene encodes tuberin, a protein involved in the pathogenesis of kidney tumors, both angiomyolipomas and renal cell carcinomas. We investigated a potential role for tuberin in regulating a key DNA repair pathway. Downregulation of tuberin in human renal epithelial cells using siRNA resulted in a marked decrease in the abundance of the 8-oxoG-DNA glycosylase (OGG1). Mouse embryonic fibroblasts deficient in tuberin (TSC2(-/-) and TSC2(+/-)) also had markedly decreased OGG1 mRNA and protein expression, as well as undetectable OGG1 activity accompanied by accumulation of 8-oxodG. Gel shift analyses and chromatin immunoprecipatation identified the transcription factor NF-YA as a regulator of OGG1 activity. The binding of NF-YA to the OGG1 promoter was significantly reduced in TSC2(-/-) compared with TSC2(+/+) cells. Introduction of TSC2 cDNA into the tuberin-deficient cells restored NF-YA and OGG1 expression. Transcriptional activity of the OGG1 promoter was also decreased in tuberin-null cells. In addition, mutation of both CAAT boxes, the sites to which NF-YA binds, completely inhibits OGG1 promoter activity. These data provide the first evidence that tuberin regulates a specific DNA repair enzyme, OGG1. This regulation may be important in the pathogenesis of kidney tumors in patients with TSC.
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PMID:Tuberin regulates the DNA repair enzyme OGG1. 1798 14

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. On the other hand, mice-deficient in the DNA repair enzyme OGG1 spontaneously develop adenoma and carcinoma. Downregulation of tuberin results in a marked decrease of OGG1 and accumulation of oxidative DNA damage, (8-oxodG) in cultured cells. In addition, tuberin haploinsufficiency is associated with the loss of OGG1 and accumulation of 8-oxodG in rat kidney tumor. Deficiency in tuberin results in decreased OGG1 and NF-YA protein expression and increased 8-oxodG in kidney tumor from TSC patients. In the current study, molecular mechanisms by which tuberin regulates OGG1 were explored. The deficiency of tuberin was associated with a significant decrease in NF-YA and loss of OGG1 in kidney tumors of Eker rat. Downregulation of tuberin by siRNA resulted in a marked decrease in NF-YA and OGG1 protein expression in human renal epithelial cells. Localization of NF-YA in wild type and tuberin-deficient cells was examined by western blot and immunostaining assays. In wild type cells, NF-YA was detected in the nucleus while in tuberin deficient cells in the cyotoplasm. Introducing adenovirus-expressing tuberin (Ad-TSC2) into tuberin-deficient cells restored the nuclear localization of NF-YA. These data define a novel mechanism of regulation of OGG1 through tuberin. This mechanism may be important in the pathogenesis of kidney tumors in patients with TSC disease.
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PMID:Molecular mechanism of regulation of OGG1: tuberin deficiency results in cytoplasmic redistribution of transcriptional factor NF-YA. 2004 97

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in humans characterized by the development of hamartomas in several organs, including renal angiomyolipomas, cardiac rhabdomyomas and subependymal giant cell astrocytomas. TSC causes disabling neurologic disorders, including epilepsy, mental retardation and autism. Brain lesions, including subependymal and subcortical hamartomas, have also been reported in TSC patients. TSC is associated with hamartomas and renal cell carcinoma (RCC) as well as sporadic tumors in TSC patient. Renal angiomyolipomas associated with TSC tend to be larger, bilateral, multifocal and present at a younger age compared with sporadic forms. Tuberous sclerosis complex of 2 genes, TSC2 encodes a protein called tuberin that normally exists in an active state and forms a heterodimeric complex with hamartin, the protein encoded by the TSC1. Deficiency ofTSC2 in Eker rat is associated with the development of tumors in several organs including kidney. The majority of renal cell tumors observed in the Eker rat originates from renal proximal tubules and are histologically similar to renal cell carcinoma in humans. On the other hand, mutations in DNA repair enzyme 8-oxoG-DNA glycosylase (OGG1) are associated with cancer. OGG1 gene is found somatically mutated in some cancer cells and is highly polymorphic among human cancers. Moreover, knockout mice in OGG1 developed spontaneously adenoma and carcinoma. We recently show that the constitutive expression of OGG1 in heterozygous (TSC2+/-) Eker rat and in angiomyolipomas kidney tissue from human is 2-3fold less than in kidney from wild-type rats and control human subjects. In addition, we show that loss of TSC2 in kidney tumor of Eker rat is associated with loss of OGG1 and accumulation significant levels of oxidative DNA damage 8-oxo-deoxyguanine suggesting that TSC2 and OGG1 play a major role in renal tumorigenesis.
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PMID:Tuberous sclerosis complex and DNA repair. 2068 97