RGD Reference Report - Fas-associated death-domain protein inhibits TNF-alpha mediated NF-kappaB activation in cardiomyocytes. - Rat Genome Database

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Fas-associated death-domain protein inhibits TNF-alpha mediated NF-kappaB activation in cardiomyocytes.

Authors: Chao, Wei  Shen, Yan  Li, Ling  Zhao, Huailong  Meiler, Steffen E  Cook, Stuart A  Rosenzweig, Anthony 
Citation: Chao W, etal., Am J Physiol Heart Circ Physiol. 2005 Nov;289(5):H2073-80. doi: 10.1152/ajpheart.01216.2004. Epub 2005 Jun 24.
RGD ID: 152025214
Pubmed: PMID:15980038   (View Abstract at PubMed)
DOI: DOI:10.1152/ajpheart.01216.2004   (Journal Full-text)

Fas-associated death-domain protein (FADD) is an adaptor molecule that links death receptors to caspase-8 in many cell types including cardiomyocytes (CMs). Although FADD has previously been reported to play an important role in CM apoptosis, the effect of FADD on CM NF-kappaB signaling, which is a proinflammatory pathway, has not been delineated. To investigate the role of FADD in CM NF-kappaB activation, we utilized adenoviral gene transfer of wild-type FADD and a truncation mutant that lacks the death-effector domain (FADD-DED) in rat CMs in vitro TNF-alpha activated NF-kappaB in CMs as demonstrated by phosphorylation and degradation of inhibitory-kappaB (IkappaB)-alpha-enhanced nuclear p65 and NF-kappaB DNA-binding activity as well as increased mRNA for the NF-kappaB-dependent adhesion molecule VCAM-1 (19 +/- 4.1-fold) as measured by quantitative RT-PCR. Gene transfer of FADD inhibited TNF-alpha-induced IkappaB-alpha phosphorylation, decreased p65 nuclear translocation and NF-kappaB DNA-binding activity, and reduced VCAM-1 transcript levels by 53-65%. Interestingly, FADD-DED exhibited a similar but weaker inhibitory effect on NF-kappaB activation. The effects of FADD on NF-kappaB were cell-type specific. FADD expression also inhibited TNF-alpha-mediated NF-kappaB activation in human endothelial cells but not in rat pulmonary artery smooth muscle cells. In contrast, FADD expression actually activated NF-kappaB in human embryonic kidney (HEK)-293 cells. In CMs, FADD inhibited NF-kappaB activation as well as phosphorylation of IkappaB-alpha and IkappaB kinase (IKK)-beta in response to cytokine stimulation or expression of the upstream kinases NF-kappaB-inducing kinase and IKK-beta. These data demonstrate that FADD inhibits NF-kappaB activation in CMs, and this inhibition likely occurs at the level of phosphorylation and activation of IKK-beta.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to tumor necrosis factor  IDA 152025214 RGD 
cellular response to tumor necrosis factor  IEP 152025214 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
double-stranded DNA binding  IDA 152025214 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Rela  (RELA proto-oncogene, NF-kB subunit)
Vcam1  (vascular cell adhesion molecule 1)


Additional Information