title: MEKK1-induced apoptosis is mediated by Smac/Diablo release from the mitochondria.
abstract: During apoptotic stimulation, the serine threonine kinase, MEKK1, is cleaved into an activated 91 kDa kinase fragment. This cleavage is mediated by caspase 3 and leads to further caspase 3 activation and apoptosis. Forced expression of the 91 kDa kinase fragment induces apoptosis through changes in membrane potential of the mitochondria mediated by permeability transition pore opening. MEKK1 activation, however, fails to release cytochrome c from the mitochondria. Herein, we determined that overexpression of MEKK1 causes mitochondrial Smac/Diablo release correlating with MEKK1-induced apoptosis. Furthermore, using siRNA that lowers Smac/Diablo expression, MEKK1-induced apoptosis was significantly reduced. Mouse embryonic fibroblast cells lacking MEKK1 expression are also resistant to etoposide-induced mitochondrial Smac/Diablo release. In contrast, etoposide-induced mitochondrial cytochrome c release was not inhibited. MEKK1 also activates the MAP kinase JNK, but MEKK1-induced mitochondrial Smac/Diablo release and apoptosis are independent of MEKK1 mediated JNK activation. Taken together, release of Smac/Diablo from the mitochondria plays a role in MEKK1-induced apoptosis.
authors.affiliation: Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Man., Canada R3N 0V9.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Mendoza
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Henson
authors.forename: Spencer B
authors.initials: SB
authors.lastname: Gibson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; C499605:Diablo protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D005047:Etoposide; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases