Molecular mechanism of regulation of OGG1: tuberin deficiency results in cytoplasmic redistribution of transcriptional factor NF-YA
Tóm tắt
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.
Tài liệu tham khảo
Nishigori C, Hattori Y, Toyokuni S: Role of reactive oxygen species in skin carcinogenesis. Antioxid Redox Signal 2004, 3:561–70.
Fortini P, Pascucci B, Parlanti E, D'Errico M, Simonelli V, Dogliotti E: 8-Oxoguanine DNA damage: at the crossroad of alternative repair pathways. Mutat Res 2003, 531:127–139.
Boiteux S, Radicella JP: The human OGG1 gene: structure, functions, and its implication in the process of carcinogenesis. Arch Biochem Biophys 2000, 377:1–8.
Dhenaut A, Boiteux S, Radicella JP: Characterization of the hOGG1 promoter and its expression during the cell cycle. Mutat Res 2000, 461:109–118.
Guibourt N, Boiteux S: Expression of the Fpg protein of Escherichia coli in Saccharomyces cerevisiae: effects on spontaneous mutagenesis and sensitivity to oxidative DNA damage. Biochimie 2000, 82:59–64.
Klungland A, Rosewell I, Hollenbach S, Larsen E, Daly G, Epe B, Seeberg E, Lindahl T, Barnes DE: Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci USA 1999, 96:13300–5.
Chevillard S, Radicella JP, Levalois C, Lebeau J, poupon MF, Oudard S, Dutrillaux B, Boiteux S: Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours. Oncogene 1998, 16:3083–3086.
Audebert M, Chevillard S, Levalois C, Gyapay G, Vieillefond A, Klijanienko J, Vielh P, El Naggar AK, Oudard S, Boiteux S, Radicella JP: Alterations of the DNA repair gene OGG1 in human clear cell carcinomas of the kidney. Cancer Res 2000, 60:4740–4744.
Lee MR, Kim SH, Cho HJ, Lee KY, Moon AR, Jeong HG, Lee JS, Hyun JW, Chung MH, You HJ: Transcription factors NF-YA regulate the induction of human OGG1 following DNA-alkylating agent methylmethane sulfonate (MMS) treatment. J Biol Chem 2004, 279:9857–9866.
Wienecke R, Konig A, DeClue JE: Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. J Biol Chem 1995, 270:16409–16414.
Mayer K, Goedbloed M, van Zijl K, Nellist M, Rott HD: Characterisation of a novel TSC2 missense mutation in the GAP related domain associated with minimal clinical manifestations of tuberous sclerosis. J Med Genet 2004, 41:1–6.
Tee AR, Anjum R, Blenis J: Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and -independent phosphorylation of tuberin. J Biol Chem 2003, 278:37288–37296.
McDorman KS, Wolf DC: Use of the spontaneous Tsc2 knockout (Eker) rat model of hereditary renal cell carcinoma for the study of renal carcinogens. Toxicol Pathol 2002, 30:675–680.
Habib SL, Phan MN, Patel SK, Li D, Monks TJ, Lau SS: Reduced constitutive 8-oxoguanine-DNA glycosylase expression and impaired induction following oxidative DNA damage in the tuberin deficient Eker rat. Carcinogenesis 2003, 24:573–582.
Habib SL, Simone S, Barnes JJ, Abboud HE: Tuberin Haploinsufficiency is Associated with the Loss of OGG1 in Rat Kidney Tumors. Molecular Cancer 2008, 7:10–14.
Habib SL, Riley DJ, Bhandari B, Mahimainathan L, Choudhury GG, Abboud HE: Tuberin Regulates the DNA Repair Enzyme OGG1. American Journal of Physiology Renal Physiology 2008, 294:F281-F290.
Habib SL: Insight into mechanism of oxidative DNA damage in angiomyolipomas from TSC patients. Molecular Cancer 2009, 8:1–10.
Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976, 72:248–254.