Tuberous sclerosis complex and DNA repair.
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.
Habib
Samy L
SL
South Texas Veterans Healthcare System, Geriatric Research, Education and Clinical Center and Department of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229, USA. habib@uthscsa.edu
D000818:Animals; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D004273:DNA, Neoplasm; D046912:Multiprotein Complexes; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D045647:DNA Glycosylases; C483741:OGG1 protein, rat; C485990:Ogg1 protein, mouse; C479058:oxoguanine glycosylase 1, human