Limits...
Molecular mechanism of regulation of OGG1: tuberin deficiency results in cytoplasmic redistribution of transcriptional factor NF-YA.

Habib SL - J Mol Signal (2009)

Bottom Line: Downregulation of tuberin results in a marked decrease of OGG1 and accumulation of oxidative DNA damage, (8-oxodG) in cultured cells.Downregulation of tuberin by siRNA resulted in a marked decrease in NF-YA and OGG1 protein expression in human renal epithelial cells.These data define a novel mechanism of regulation of OGG1 through tuberin.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus

Deficiency in tuberin is associated with significant decrease in NF-YA and loss of OGG1 expression in kidney tumor of Eker rats. A. Immunoblot analysis of tuberin, NF-YA and OGG1 protein expression in normal kidney of wild type rats and tumor kidney tissue from Eker rats. Actin was used as loading control. B. Histograms represent means ± SE (n = 3). Significant difference from wild type rat is indicated by ** P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2807420&req=5

Figure 1: Deficiency in tuberin is associated with significant decrease in NF-YA and loss of OGG1 expression in kidney tumor of Eker rats. A. Immunoblot analysis of tuberin, NF-YA and OGG1 protein expression in normal kidney of wild type rats and tumor kidney tissue from Eker rats. Actin was used as loading control. B. Histograms represent means ± SE (n = 3). Significant difference from wild type rat is indicated by ** P < 0.01.

Mentions: To determine the effect of tuberin on expression of NF-YA, kidney from wild type rats and tumor kidney tissue from Eker rats were examined by western blot analysis. Loss of tuberin was associated with loss of OGG1 and significant decrease in NF-YA in tumor kidney tissue of Eker rats (Fig. 1). These data suggest that tuberin is an important tumor suppressor protein involve in the regulation of OGG1 abundance through NF-YA.


Molecular mechanism of regulation of OGG1: tuberin deficiency results in cytoplasmic redistribution of transcriptional factor NF-YA.

Habib SL - J Mol Signal (2009)

Deficiency in tuberin is associated with significant decrease in NF-YA and loss of OGG1 expression in kidney tumor of Eker rats. A. Immunoblot analysis of tuberin, NF-YA and OGG1 protein expression in normal kidney of wild type rats and tumor kidney tissue from Eker rats. Actin was used as loading control. B. Histograms represent means ± SE (n = 3). Significant difference from wild type rat is indicated by ** P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2807420&req=5

Figure 1: Deficiency in tuberin is associated with significant decrease in NF-YA and loss of OGG1 expression in kidney tumor of Eker rats. A. Immunoblot analysis of tuberin, NF-YA and OGG1 protein expression in normal kidney of wild type rats and tumor kidney tissue from Eker rats. Actin was used as loading control. B. Histograms represent means ± SE (n = 3). Significant difference from wild type rat is indicated by ** P < 0.01.
Mentions: To determine the effect of tuberin on expression of NF-YA, kidney from wild type rats and tumor kidney tissue from Eker rats were examined by western blot analysis. Loss of tuberin was associated with loss of OGG1 and significant decrease in NF-YA in tumor kidney tissue of Eker rats (Fig. 1). These data suggest that tuberin is an important tumor suppressor protein involve in the regulation of OGG1 abundance through NF-YA.

Bottom Line: Downregulation of tuberin results in a marked decrease of OGG1 and accumulation of oxidative DNA damage, (8-oxodG) in cultured cells.Downregulation of tuberin by siRNA resulted in a marked decrease in NF-YA and OGG1 protein expression in human renal epithelial cells.These data define a novel mechanism of regulation of OGG1 through tuberin.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus