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1 Laboratory of Kidney and Electrolyte Metabolism, National Heart Lung and Blood Institute, Bethesda, MD, USA
2 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: zzhang3{at}vcu.edu.
High NaCl activates the transcription factor, 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 ATM kinase through autophosphorylation on Ser1981. 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 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 n-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. Conclusion: Activation of ATM contributes to high NaCl-induced nuclear translocation of TonEBP/OREBP.
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