Ceramide induces p38 MAPK-dependent apoptosis and Bax translocation via inhibition of Akt in HL-60 cells.
Ceramide induces apoptosis through caspase activation, cytochrome c release, and Bax translocation in HL-60 cells. However, the upstream signal transduction pathways that induce Bax translocation during ceramide-mediated apoptosis have not been well defined yet. In this study, the activation of p38 mitogen-activated protein kinase (MAPK) was found to be critical for the induction of apoptosis and subcellular redistribution of Bax. Pharmacological inhibition of p38 MAPK with SB203580 or expression of a dominant-negative p38 MAPK attenuated DNA fragmentation, caspase-3 activation, and Bax translocation in response to ceramide. Overexpression of Akt also led to suppression of Bax translocation to mitochondria during ceramide-induced apoptosis in HL-60 cells. We also provide evidence for cross-talk between p38 MAPK and Akt pathways. Expression of myr-Akt or inhibition of phosphatidylinositol 3-kinase (PI3K) with LY294002 had no effect on p38 MAPK activation by ceramide as assessed by phosphorylation, while inhibition of p38 MAPK by a pharmacological inhibitor or a dominant-negative p38 inhibited Akt dephosphorylation in response to ceramide, suggesting that ceramide-induced p38 MAPK activation negatively regulates the Akt pathway.
Kim
Hae Jong
HJ
Division of Biochemistry, College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
Oh
Ji Eun
JE
Kim
Sang Woo
SW
Chun
Young Jin
YJ
Kim
Mie Young
MY
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C494826:BAX protein, human; D002518:Ceramides; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; C093642:SB 203580