title: FOXO3a turns the tumor necrosis factor receptor signaling towards apoptosis through reciprocal regulation of c-Jun N-terminal kinase and NF-kappaB.
abstract: OBJECTIVE
  We evaluated the full range effects of FOXO3a in endothelial cells (ECs) by microarray analysis and investigated the role of FOXO3a regulating TNF receptor signaling pathway.
  
  
  RESULTS
  Human umbilical vein endothelial cells (HUVECs) were transfected with adenoviral vectors expressing constitutively active FOXO3a (Ad-TM-FOXO3a). Ad-TM-FOXO3a transfection caused remarkable apoptosis, which were accompanied with upregulation of genes related with TNF receptor signaling, such as TNF-alpha, TANK (TRAF-associated NF-kappaB activator), and TTRAP (TRAF and TNF receptor-associated protein). Furthermore, kappaB-Ras1 (IkappaB-interacting Ras-like protein-1) which is known to block IkappaB degradation was found increased, and intranuclear translocation of NF-kappaB was inhibited. GADD45beta and XIAP, negative regulators of c-Jun N-terminal kinase (JNK), were suppressed and JNK activity was increased. Attenuation of TNF signaling pathway either by blocking antibody for TNF receptor or by blocking JNK with DMAP (6-dimethylaminopurine) or Ad-TAM67 (dominant negative c-Jun) cotransfection, significantly reduced FOXO3a-induced apoptosis. Finally, treatment of vasculature with heat shock, an activator of endogenous FOXO3a, resulted in EC apoptosis, which was completely rescued by Ad-TAM67.
  
  
  CONCLUSIONS
  FOXO3a promotes apoptosis of ECs, through activation of JNK and suppression of NF-kappaB. These data identify a novel role of FOXO3a to turn TNF receptor signaling to a proapoptotic JNK-dependent pathway.
authors.affiliation: Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Seock-Won
authors.initials: SW
authors.lastname: Youn
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Kyung-Woo
authors.initials: KW
authors.lastname: Park
authors.forename: Chang-Il
authors.initials: CI
authors.lastname: Hwang
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002339:Carotid Arteries / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases