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TNF signaling induces the tumor necrosis factor receptor‐1 (TNFR1) complex with the members of death‐inducing signaling complex (DISC) to localize the nucleus in hepatocytes
Author(s) -
Eum HyunAe,
Vallabhaneni Raghuveer,
Loughran Patricia A.,
Billiar Timothy R.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1238.8
Subject(s) - tradd , fadd , nucleus , microbiology and biotechnology , tumor necrosis factor receptor 1 , tumor necrosis factor alpha , traf2 , signal transduction , apoptosis , cytoplasm , stimulation , chemistry , biology , programmed cell death , caspase , neuroscience , immunology , death domain , biochemistry , tumor necrosis factor receptor
Activation of TNFR1 triggers a cascade of signaling events, including assembly of the DISC, that culminate in cellular apoptosis. Although key elements of DISC are well defined, the molecular mechanisms DISC formation and its subcelluar localization in TNFR1 signaling are poorly defined. Therefore, the aim of this study is to investigate the subcellular localization of TNFR1 and components of the DISC on TNF‐induced apoptosis. We hypothesized that the TNFR1 and the DISC components would be located within the nucleus and the mitochondria after initiation of TNF induced signaling. Sprague‐Dawley rat hepatocytes were used for all experiments. TNF (2000 units/ml) and actinomycin D (Act D; 200 ng/ml) were utilized to induce apoptosis. We demonstrated that TNFR1 recruits TRADD, FADD, and caspase‐8 to establish the DISC in the cytoplasm by both TNF and TNF/Act D stimulation. We also evaluated whether TNFR1 complex with DISC components are localize in the nucleus. The stimulation of TNF by itself resulted in caspase‐8 immunoprecipitation (IP) with TNFR1 into the nucleus within 30 min. However, the TNF/Act D treatment caused the caspase‐8 to Co‐IP with TNFR1 to even more quickly localize into the nucleus. Although TRADD is presented in the nucleus, it did not Co‐IP with TNFR1 in the nucleus with either TNF or TNF/Act D stimulation. These novel findings point to the importance of nucleus in the early TNF cell signaling cascade.