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. 2008 Jan;28(1):112-20.
doi: 10.1161/ATVBAHA.107.153304. Epub 2007 Nov 21.

FOXO3a turns the tumor necrosis factor receptor signaling towards apoptosis through reciprocal regulation of c-Jun N-terminal kinase and NF-kappaB

Hae-Young Lee  1 , Seock-Won Youn, Ju-Young Kim, Kyung-Woo Park, Chang-Il Hwang, Woong-Yang Park, Byung-Hee Oh, Young-Bae Park, Kenneth Walsh, Jeong-Sun Seo, Hyo-Soo Kim
Affiliations

FOXO3a turns the tumor necrosis factor receptor signaling towards apoptosis through reciprocal regulation of c-Jun N-terminal kinase and NF-kappaB

Hae-Young Lee et al. Arterioscler Thromb Vasc Biol. 2008 Jan.

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.

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