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FOXO3a turns the tumor necrosis factor receptor signaling towards apoptosis through reciprocal regulation of c-Jun N-terminal kinase and NF-kappaB
Cited 41 time in
Web of Science
Cited 43 time in Scopus
- Authors
- Issue Date
- 2007-11-23
- Publisher
- American Heart Association
- Citation
- Arterioscler Thromb Vasc Biol. 2008;28(1):112-120
- Keywords
- 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
- 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. 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.
- ISSN
- 1524-4636 (Electronic)
- Language
- English
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