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1 Medicine, Baylor College of Medicine, Houston, Texas, United States
2 Biochemistry and Cell Biology, Rice University, Houston, Texas, United States
* To whom correspondence should be addressed. E-mail: sheikh{at}bcm.tmc.edu.
Mitogen-activated protein (MAP) kinase cascades contain a trio of kinases MKKK 
MKK MAPK that mediate a variety of cellular responses to different signals including hypertonicity. The signaling response to hypertonicity is conserved across evolution from yeast to mammals in that; it involves activation of p38/SAPK. However, very little is known about which upstream protein kinases mediate activation of p38 by hypertonicity in mammals. The MKKKs, MEKK3 and MEKK4 are upstream regulators of p38 in many cells. To investigate these signaling proteins as potential activators of p38 in the hypertonicity response, we generated stably transfected MDCK cells that express activated versions of MEKK3 or MEKK4; utilized RNAi to deplete MEKK3 and employed pharmacological inhibition of p38 kinase. MEKK3-transfected cells demonstrated increased betaine transporter (BGT1) mRNA levels and upregulated tonicity enhancer (TonE)-driven luciferase activity under isotonic (basal) and hypertonic conditions, compared to empty vector-transfected controls; siRNA-mediated depletion of MEKK3 down-regulated the activity of p38 kinase and decreased the expression of BGT1 mRNA. P38 kinase inhibition abolished the effects of MEKK3 activation on BGT1 induction. In contrast, the response to hypertonicity in MEKK4-kA-transfected cells was similar to that observed in empty vector-transfected controls. Our data are consistent with the existence of an input from MEKK3 p38 kinase TonE.
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