Rel/NF-kappaB transcription factors protect against tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by up-regulating the TRAIL decoy receptor DcR1.
Rel/nuclear factor (NF)-kappaB transcription factors play a major role in the regulation of programmed cell death. A few anti-apoptotic Rel/NF-kappaB target genes have been characterized; they act either downstream in the apoptotic pathway or upstream, for example at the tumor necrosis factor (TNF) receptor level. We found using DNA arrays, reverse transcription-polymerase chain reaction, and immunofluorescence that Rel/NF-kappaB factors up-regulate DcR1, a receptor for TNF-related apoptosis-inducing ligand (TRAIL), a cytokine of the TNF family that induces apoptosis in tumor cells. Four related receptors bind TRAIL, two death receptors (DR4 and DR5) that signal apoptosis and two decoy receptors (DcR1 and DcR2) that act as dominant negative inhibitors of TRAIL-mediated apoptosis. DcR1 is devoid of an intracellular domain and is anchored at the cell surface membrane by a glycophospholipid. Our results indicate that overexpression of cRel or activation of endogenous Rel/NF-kappaB factors by TNFalpha in HeLa cells up-regulates DcR1 without changing the expression of DcR2, DR4, and DR5 and makes cells resistant against TRAIL-induced apoptosis. This resistance is a consequence of DcR1 up-regulation, because it was abolished when DcR1 was removed from the cell surface by a phosphatidylinositol phospholipase C. Therefore, Rel/NF-kappaB transcription factors could regulate the sensitivity of cells to TRAIL, by controlling the ratio of TRAIL-decoy to -death receptors.
Bernard
D
D
Formation de Recherche en Evolution 2353 and Unite Mixte de Recherche 8526 CNRS/Institut Pasteur de Lille/Université Lille 2, Institut de Biologie de Lille, 1 rue Calmette, 59021 Lille Cedex, France.
Quatannens
B
B
Vandenbunder
B
B
Abbadie
C
C
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D051996:Transcription Factor RelA; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D051996:Transcription Factor RelA; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha