title: Constitutive activation of AKT pathway inhibits TNF-induced apoptosis in mitochondrial DNA-deficient human myelogenous leukemia ML-1a.
abstract: TNF plus protein synthesis inhibitor cycloheximide-induced apoptosis in human myelogenous leukemia ML-1a but not in C19, respiration minus mitochondrial DNA-deficient C19 cells, derived from ML-1a. To investigate how mitochondrial DNA depletion inhibits apoptosis, we investigated AKT. Both AKT and its phosphorylated form were observed only in C19, indicating that depletion of mtDNA increased protein and the active form of AKT. Treatment of C19 with LY294002, which inhibits PI-3 kinase and inhibits AKT, significantly increased apoptosis induction by TNF plus cycloheximide and eliminated phosphorylation of AKT. These results indicate that AKT activation was induced by the depletion of mtDNA and inhibited TNF-induced apoptosis.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA.
authors.forename: Seigo
authors.initials: S
authors.lastname: Suzuki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Naito
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asano
authors.forename: Teresa T
authors.initials: TT
authors.lastname: Evans
authors.forename: Shrikanth A G
authors.initials: SA
authors.lastname: Reddy
authors.forename: Masahiro
authors.initials: M
authors.lastname: Higuchi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D002999:Clone Cells; D003513:Cycloheximide / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D002867:Chromones; D004272:DNA, Mitochondrial; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003513:Cycloheximide; D051057:Proto-Oncogene Proteins c-akt