Phosphatidylinositol 3-Kinase Mediates Activation of ATM by High NaCl and by Ionizing Radiation: Role in Osmoprotective Transcriptional Regulation

High NaCl causes DNA double-strand breaks and activates the transcription factor, TonEBP/OREBP, resulting in increased transcription of several protective genes, including those involved in accumulation of compatible organic osmolytes. Several kinases are known to contribute to signaling activation of TonEBP/OREBP, including ATM, which is a member of the phosphatidylinositol 3-kinase (PI3K)-like kinase family and is activated by DNA doublestrand breaks. The purpose of the present studies was to investigate a possible role of PI3K Class IA (P13K-IA). We found that high NaCI increases PI3K-IA lipid kinase activity. Inhibiting PI3K-IA either by expressing a dominant negative of its regulatory subunit, p85, or by small interfering RNA-mediated knockdown of its catalytic subunit, p110α, reduces high NaCI-induced increases in TonEBP/OREBP transcriptional activity and transactivation, but not nuclear translocation of TonEBP/OREBP, or increases in its abundance. Further, suppression of PI3K-IA inhibits the activation of ATM that is caused by either ionizing radiation or high NaCI. High NaCI-induced increase in TonEBP/OREBP activity is reduced equally by inhibition of ATM or PI3K-IA, and the effects are not additive. The conclusions are as follows: (i) PI3K-IA activity is necessary for both high NaCI- and ionizing radiation-induced activation of ATM and (ii) high NaCI activates PI3K-IA, which, in turn, contributes to full activation of TonEBP/OREBP via ATM.