Habib Samy L
South Texas Veterans Healthcare System, Geriatric Research, Education and Clinical Center, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
J Mol Signal. 2009 Dec 29;4:8. doi: 10.1186/1750-2187-4-8.
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.
结节性硬化症（TSC）由两个肿瘤抑制基因TSC - 1或TSC - 2之一的缺陷引起。TSC - 2基因编码结节蛋白，该蛋白参与肾肿瘤（血管平滑肌脂肪瘤和肾细胞癌）的发病机制。另一方面，DNA修复酶OGG1缺陷的小鼠会自发发生腺瘤和癌。在培养细胞中，结节蛋白的下调导致OGG1显著减少和氧化性DNA损伤（8 - 氧代鸟嘌呤）的积累。此外，结节蛋白单倍体不足与大鼠肾肿瘤中OGG1的缺失和8 - 氧代鸟嘌呤的积累有关。结节蛋白缺陷导致TSC患者肾肿瘤中OGG1和NF - YA蛋白表达降低以及8 - 氧代鸟嘌呤增加。在本研究中，探讨了结节蛋白调节OGG1的分子机制。在Eker大鼠的肾肿瘤中，结节蛋白的缺陷与NF - YA的显著减少和OGG1的缺失有关。通过小干扰RNA（siRNA）下调结节蛋白导致人肾上皮细胞中NF - YA和OGG1蛋白表达显著降低。通过蛋白质免疫印迹和免疫染色试验检测野生型和结节蛋白缺陷细胞中NF - YA的定位。在野生型细胞中，NF - YA在细胞核中被检测到，而在结节蛋白缺陷细胞中则在细胞质中。将表达结节蛋白的腺病毒（Ad - TSC2）引入结节蛋白缺陷细胞可恢复NF - YA的核定位。这些数据确定了一种通过结节蛋白调节OGG1的新机制。这种机制可能在TSC病患者肾肿瘤的发病机制中起重要作用。
