Transcriptional Repression of Taurine Transporter Gene (TauT) by p53 in Renal Cells

Xiaobin Han,Andrea Budreau Patters,Russell W Chesney

doi:10.1074/jbc.m205939200

Abstract

Taurine, an intracellular osmolyte whose body pool size is adaptively regulated by the kidney, is required for normal renal development. Overexpression of the p53 tumor suppressor gene in p53 transgenic mice results in renal malformation, suggesting that altered expression of certain p53 target gene(s) involved in renal development may be responsible. This study shows that the taurine transporter gene (TauT) is a transcriptional target of p53. Expression of TauT was decreased after activation of p53 by doxorubicin, a DNA-damaging drug, in 293 and NRK-52E renal cells. TauT promoter activity was decreased 5-10-fold by cotransfection of a full-length TauT promoter-reporter construct with p53, which was reversed by cotransfection with a mutant p53 (p53-281). Electrophoretic mobility shift assays using nuclear extracts from p53-expressing (10)1val cells showed a putative p53-binding site in the TauT promoter region, which bound to the p53 in electrophoretic mobility shift assays. Mutation of this p53 consensus sequence abolished binding of p53. These results demonstrate that TauT may represent a downstream target gene of p53 that could link the roles of p53 in renal development and apoptosis.

Highlights

The ␤-amino acid taurine plays an important role in cell volume regulation
Electrophoretic mobility shift assays using nuclear extracts from p53-expressing [10]1val cells showed a putative p53-binding site in the taurine transporter gene (TauT) promoter region, which bound to the p53 in electrophoretic mobility shift assays. Mutation of this p53 consensus sequence abolished binding of p53. These results demonstrate that TauT may represent a downstream target gene of p53 that could link the roles of p53 in renal development and apoptosis
Varmus’ group has found that transgenic mice overexpressing p53 undergo progressive renal failure through a novel mechanism by which p53 seems to alter cellular differentiation, rather than by growth arrest or the direct induction of apoptosis [10]. These findings suggest that altered expression of certain p53 target gene(s) involved in renal development may be responsible for p53-induced progressive renal failure in p53 transgenic mice

Summary

Introduction

The ␤-amino acid taurine plays an important role in cell volume regulation. The total body pool of taurine is controlled at the brush border surface of the renal proximal tubule by an NaCl-dependent transporter that is up- or down-regulated by the availability of dietary taurine or its precursor amino acids, cysteine and methionine [1]. Expression of TauT was decreased after activation of p53 by doxorubicin, a DNA-damaging drug, in 293 and NRK-52E renal cells. TauT Is Down-regulated by p53—Our initial experiments examined whether doxorubicin, a DNA-damaging drug, would induce endogenous p53 expression in 293 and NRK-52E renal cells.

Results

Conclusion