Nuclear factor-kappa B-inducible death effector domain-containing protein suppresses tumor necrosis factor-mediated apoptosis by inhibiting caspase-8 activity.
Activation of the transcription factor nuclear factor-kappa B (NF-kappa B) has been found to play an essential role in the inhibition of tumor necrosis factor (TNF)-mediated apoptosis. NF-kappa B regulates several antiapoptotic molecules including inhibitors of apoptosis, Bcl-2 family proteins (A1 and Bcl-X(L))(,) and IEX-IL. Here we report that the expression of a small death effector domain (DED)-containing protein, NDED (NF-kappa B-inducible DED-containing protein), depends on the activation of NF-kappa B. The inhibition of NF-kappa B by I kappa B alpha, a natural inhibitor of NF-kappa B, suppressed NDED mRNA expression induced by TNF. The restoration of NDED in NF-kappa B null cells inhibited TNF-induced apoptosis. Intriguingly, unlike the caspase-8 inhibitor cellular FADD-like interleukin-1 beta converting enzyme-inhibitory protein (c-FLIP), NDED suppressed TNF-mediated apoptosis by inhibiting TNF-induced caspase-8 enzymatic activity but not the processing of caspase-8. Furthermore, NDED could not inhibit etoposide-mediated apoptosis that is independent of caspase-8 activation. Our results provide the first demonstration that NF-kappa B transcriptionally induces the DED-containing protein to suppress TNF-mediated apoptosis by inhibiting caspase-8 activity, which offers new insight into the antiapoptotic mechanism of NF-kappa B.
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Laboratory of Molecular Signaling and Apoptosis, the Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA.
Ouyang
H
H
Lopatin
D
D
Polver
P J
PJ
Wang
C Y
CY
D017209:Apoptosis / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases