Changes in the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling associated with the induction of apoptosis.
Trigeminal neurinoma cells were used to characterize the involvement of ERK, JNK, p38 and phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathways in the induction of apoptosis. Activation of JNK by anisomycin, the inhibition of ERK activation by PD098059 or a blockage of the PI3-K/Akt pathway by wortmannin or LY294002 alone, was not sufficient for the induction of apoptosis. Apoptosis was rapidly induced when the activation of JNK was coupled with the inhibition of PI3-K/Akt, and the induction was further enhanced by a concurrent inhibition of ERK activation. The p38 inhibitor, PD169316, reduced the activities of ERK and Akt. Rapid induction of apoptosis occurred when the inhibition of p38 was coupled with JNK activation, and a concurrent inhibition of PI3-K/Akt potentiated the induction. Apoptosis was also induced without JNK activation, though at a slower rate, by a combined treatment with PD169316 and LY294002. A concomitant inhibition of ERK and Akt activation induced apoptosis without JNK activation, although with a considerable delay of its onset. These results suggest that ERK, JNK, p38 and PI3-K/Akt signaling pathways interact to form an integrated network, and the induction of apoptosis requires coordinated changes in these signaling pathways.
Marushige
K
K
Department of Pathology, Michigan State University, East Lansing 48824, USA.
Marushige
Y
Y
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D017209:Apoptosis; D048429:Cell Size / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009442:Neurilemmoma / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D000730:Androstadienes; D000841:Anisomycin; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494920:Akt1 protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one