Molecular mechanism of regulation of OGG1: tuberin deficiency results in cytoplasmic redistribution of transcriptional factor NF-YAReport as inadecuate




Molecular mechanism of regulation of OGG1: tuberin deficiency results in cytoplasmic redistribution of transcriptional factor NF-YA - Download this document for free, or read online. Document in PDF available to download.

Journal of Molecular Signaling

, 4:8

First Online: 29 December 2009Received: 10 September 2009Accepted: 29 December 2009

Abstract

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.

AbbreviationsTSC2tuberous sclerosis complex-2

OGG18-oxoG-DNA glycosylase

RCCrenal cell carcinoma

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Author: Samy L Habib

Source: https://link.springer.com/







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