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Title 

Role of FLASH in caspase-8-mediated activation of NF-κB: dominant-negative function of FLASH mutant in NF-κB signaling pathway

Authors 

J I JunC W ChungH J LeeJ O PyoKee Nyung LeeNam-Soon KimYong Sung KimHyang Sook YooT H LeeE KimY K Jung

Publisher 

Nature Publishing Group

Issue Date 

2005

Citation 

Oncogene, vol. 24, no. 4, pp. 688-696

Keywords 

caspase-8dominant negativeFLASHNF-κBSiRNAcaspase 8immunoglobulin enhancer binding proteinphorbol 13 acetate 12 myristateenzyme activationcalcium-binding proteins

Abstract 

Caspase-8 is the most receptor-proximal, upstream caspase in the caspase cascade and plays a key role in cell death triggered by various death receptors. Here, we addressed the role of endogenous caspase-8 in tumor necrosis factor (TNF)-α-induced activation of NF-κB. Direct targeting of caspase-8 with siRNA and antisense (AS) approaches abolished TNF-α-induced activation of NF-κB in NIH3T3, HeLa, and HEK293 cells as determined with luciferase reporter gene and cell fractionation assays. Reconstitution of caspase-8-deficient C33A cells with processing-defective (P/D) mutant of caspase-8 sensitized the cells to TNF-α for NF-κB activation. In contrast to wild-type caspase-8, death effector domain mutant replacing Asp73 with Ala (caspase-8 (D73A)) failed to activate NF-κB and to bind FLICE-associated huge protein (FLASH) in vitro and in vivo. Instead, caspase-8 (D73A) mutant bound to caspase-8 and blocked NF-κB activation triggered by TNF-α and caspase-8. In addition, expression of an NF-κB-activating domain-deletion mutant of FLASH or transfection of FLASH AS oligonucleotides abolished TNF-α and caspase-8, but not phorbol 12-myristate 13-acetate, -induced activation of NF-κB. Further, immunoprecipitation assays showed that caspase-8 formed triple complex with TRAF2 and FLASH. Taken together, these results suggest that endogenous caspase-8 mediates TNF-α-induced activation of NF-κB via FLASH.

ISSN 

0950-9232

Link 

http://dx.doi.org/10.1038/sj.onc.1208186

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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