Peroxynitrite-induced p38 MAPK pro-apoptotic signaling in enterocytes.
Enterocyte apoptosis in necrotizing enterocolitis is partly due to the elaboration of toxic intermediates of nitric oxide (NO), such as peroxynitrite (PN). Because p38 mitogen-activated protein kinase (MAPK) and serine-threonine kinase (AKT) are well-characterized pro- and anti-apoptotic mediators, respectively, we hypothesized that PN could induce enterocyte apoptosis via activation of p38 and deactivation of AKT. To test this hypothesis, the rat intestinal cell line, IEC-6, was treated with PN. PN caused phosphorylation of p38, its upstream activator, MKK3/6, and downstream effector, transcription factor ATF-2. PN-induced apoptosis was inhibited by the p38 inhibitor, SB202190, and by p38 siRNA. PN decreased AKT phosphorylation; this effect was abrogated by pre-treatment with SB202190 or p38 siRNA. PN exposure also increased the activity of the protein phosphatase 2A (PP2A). These data demonstrate that PN-mediated apoptosis depends on the p38 pathway and that p38 mediates deactivation of AKT survival pathways possibly by the involvement of PP2A.
Guner
Yigit S
YS
Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Ochoa
Christian J
CJ
Wang
Jin
J
Zhang
Xiaoru
X
Steinhauser
Sarah
S
Stephenson
Lydia
L
Grishin
Anatoly
A
Upperman
Jeffrey S
JS
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D020345:Enterocolitis, Necrotizing / Q000201:enzymology*; D020895:Enterocytes / Q000187:drug effects / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D030421:Peroxynitrous Acid; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole