Ataxia telangiectasia-mutated, a DNA damage-inducible kinase, contributes to high NaCl-induced nuclear localization of transcription factor TonEBP/OREBP

作者：Zhang Z^*; Ferraris JD; Irarrazabal CE; Dmitrieva NI; Park JH; Burg MB

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2005, 289(3): F506-F511.

DOI：10.1152/ajprenal.00417.2004

• ataxia telangiectasia-mutated kinase
• tonicity
• responsive enhancer/osmotic response element binding protein
• wortmannin
• AT cells

Zhang, Zheng, Joan D. Ferraris, Carlos E. Irarrazabal, Natalia I. Dmitrieva, Jong-Hwan Park, and Maurice B. Burg. Ataxia telangiectasia-mutated, a DNA damage-inducible kinase, contributes to high NaCl-induced nuclear localization of transcription factor TonEBP/OREBP. Am J Physiol Renal Physiol 289: F506 - F511, 2005. First published April 19, 2005; doi: 10.1152/ ajprenal. 00417.2004. - High NaCl activates the transcription factor tonicity-responsive enhancer/osmotic response element binding protein (TonEBP/ OREBP) by increasing its abundance and transactivation, the latter signaled by a variety of protein kinases. In addition, high NaCl causes TonEBP/OREBP to translocate into the nucleus, but little is known about the signals directing this translocation. The result is increased transcription of protective genes, including those involved in accumulation of organic osmolytes. High NaCl also damages DNA, and DNA damage activates ataxia telangiectasia-mutated (ATM) kinase through autophosphorylation on serine 1981. We previously found that ATM is involved in the high NaCl-induced increase in TonEBP/OREBP transactivation. The purpose of the present studies was to test whether ATM is also involved in high NaCl-induced TonEBP/OREBP nuclear translocation. We quantified TonEBP/OREBP in nuclear and cytoplasmic extracts from cultured cells by Western blot analysis. In COS-7 cells, wortmannin, an inhibitor of ATM, reduces high NaCl-induced nuclear translocation of TonEBP/OREBP. We used AT cells (in which ATM is inactive) to test the specificity of this effect. Nuclear translocation of native TonEBP/OREBP and of its recombinant NH(2)-terminal rel homology domain, which contains the nuclear localization signal, is reduced in AT cells and is restored when the cells are reconstituted with functional ATM. In conclusion, activation of ATM contributes to high NaCl-induced nuclear translocation of TonEBP/OREBP.

• 出版日期2005-9
• 单位NIH