title: MEKK1-induced apoptosis requires TRAIL death receptor activation and is inhibited by AKT/PKB through inhibition of MEKK1 cleavage.
abstract: MEK kinase 1 (MEKK1) induces apoptosis through the activation of caspases. The mechanism for MEKK1-induced apoptosis involves caspase-mediated cleavage of MEKK1, releasing a pro-apoptotic 91 kDa kinase fragment that serves to further amplify caspase activation in a feedback loop. Both cleavage of MEKK1 and increased expression of death receptor 4 (DR4, TRAILR1) and death receptor 5 (DR5, TRAILR2) occur following exposure of cells to genotoxins. Overexpression of kinase inactive MEKK1 inhibits MEKK1-mediated apoptosis and effectively blocks death receptor upregulation following etoposide treatment. Herein, we investigate the role of death receptor activation and the ability of AKT/PKB (AKT) to inhibit cell death in MEKK1-induced apoptosis. We show that by preventing DR4 and DR5 activation through expression of decoy receptor 1 (DcR1) and dominant negative FADD, we inhibit MEKK1-induced apoptosis. Furthermore, expression of 91 kDa MEKK1 increased DR4 and FAS mRNA and protein levels. MEKK1-induced apoptosis is amplified by blocking PI-3 kinase activation and overexpression of AKT blocked both MEKK1-induced apoptosis and caspase activation. AKT overexpression also prevented the cleavage of endogenous MEKK1 by genotoxins. AKT did not, however, block MEKK1-induced JNK activation, showing that regulation of the JNK pathway by MEKK1 is independent of its role in regulation of apoptosis. Thus, MEKK1-induced apoptosis requires TRAIL death receptor activation and is blocked by AKT through inhibition of MEKK1 cleavage.
authors.affiliation: Department of Pharmacology, University of Colorado, 2400 East Ninth Street, Denver, Colorado, CO 80262, USA.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Bild
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Mendoza
authors.forename: Erika M
authors.initials: EM
authors.lastname: Gibson
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.forename: Jacylyn
authors.initials: J
authors.lastname: Villanueva
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Garrington
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
authors.forename: Spencer B
authors.initials: SB
authors.lastname: Gibson
mesh_terms: D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics
chemical_list: D053148:Caspase 3; D020169:Caspases; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C494918:AKT1 protein, human; C482576:MAP3K1 protein, human; C505407:CASP3 protein, human