Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 275, Issue 32, Pages 24357-24366Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M000811200
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In HeLa cells, induction of apoptosis and nuclear factor kappa B (NF-kappa B) activation initiated by TRAIL/Apo2L or the agonistic Apol/Fas-specific monoclonal antibody anti-APO-1 require the presence of cycloheximide (CHX). Inhibition of caspases prevented TRAIL/anti-APO-1-induced apoptosis, but not NF-kappa B activation, indicating that both pathways bifurcate upstream of the receptor-proximal caspase-8, Under these conditions, TRAIL and anti-APO-1 up-regulated the expression of the known MF-kappa B targets interleukin-8, cellular inhibitor of apoptosis 2 (cIAP2), and TRAF1 (TRAF, tumor necrosis factor receptor-associate factor). In the presence of CHX, the stable overexpression of a deletion mutant of the Fas-associated death domain molecule FALL comprising solely the death domain of the molecule but lacking its death effector domain (FADD-(80-208)) led to the same response pattern as TRAIL or anti-APO-1 treatment. Moreover, the ability of death receptors to induce NF-kappa B activation was drastically reduced in a FADD-deficient Jurkat cell line. TRAIL-, anti-APO-1-, and FADD-(80 -208)-initiated gene induction was blocked by a dominant-negative mutant of TRAF2 or the p38 kinase inhibitor SB203580, similar to tumor necrosis factor receptor-1-induced NF-kappa B activation. CHX treatment rapidly down-regulated endogenous cFLIP protein levels, and overexpression of cellular FLICE inhibitory protein (cFLIP) inhibited death receptor-induced NF-kappa B activation. Thus, a novel functional role of cFLIP as a negative regulator of gene induction by death receptors became apparent.
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