S-Space College of Medicine/School of Medicine (의과대학/대학원) Internal Medicine (내과학전공) Journal Papers (저널논문_내과학전공)
FOXO3a turns the tumor necrosis factor receptor signaling towards apoptosis through reciprocal regulation of c-Jun N-terminal kinase and NF-kappaB
- Lee, Hae-Young; Youn, Seock-Won; Kim, Ju-Young; Park, Kyung-Woo; Hwang, Chang-Il; Park, Woong-Yang; Oh, Byung-Hee; Park, Young-Bae; Walsh, Kenneth; Seo, Jeong-Sun; Kim, Hyo-Soo
- Issue Date
- American Heart Association
- Arterioscler Thromb Vasc Biol. 2008 Jan;28(1):112-20. Epub 2007 Nov 21.
- Adenoviridae/genetics; Animals; Apoptosis/*physiology; Carotid Arteries/physiology; Cells, Cultured; Endothelial Cells/*metabolism; Forkhead Transcription Factors/*physiology; Genetic Vectors; Humans; JNK Mitogen-Activated Protein Kinases/*metabolism; NF-kappa B p50 Subunit/*metabolism; Oligonucleotide Array Sequence Analysis; Rats; Receptors, Tumor Necrosis Factor/*physiology; Signal Transduction; Transfection; Tumor Necrosis Factor-alpha/*metabolism; Umbilical Veins/cytology; Up-Regulation
- 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. METHODS AND 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.
- 1524-4636 (Electronic)