Overexpression of the 'silencer of death domain', SODD/BAG-4, modulates both TNFR1- and CD95-dependent cell death pathways.
The involvement of SODD/BAG-4 was studied in TNFR1 signaling, using SODD/BAG-4- overexpressing HeLa cells as a cellular model. Stable transfection of a SODD/BAG-4 cDNA leads to increased levels of the full-length 70-kDa protein and additional C-terminal fragments as well as altered expression of BAG-1. Concomitantly, the protein amounts of both the TNFR1 and, unexpectedly, the CD95 receptors are elevated. These biochemical changes are paralleled and confirmed by a reduced cellular sensitivity to treatment with extracellular TNFalpha and CD95 ligand. Moreover, ATP depletion by oligomycin is less toxic in SODD/BAG-4 overexpressing clones. The radiosensitivity is reduced in some, but not in all of these clones. Our results indicate that SODD/BAG-4 is not only a silencer of TNFR1 but also a modulator of CD95 activity, regulating the balance of both death-promoting and -depressing signals.
Eichholtz-Wirth
Hedda
H
GSF-National Research Center for Environment and Health, Institute of Radiobiology, Ingolstaedter Landstr 1, D-85764, Neuherberg, Germany. eichholtz@gsf.de
Fritz
Eberhard
E
Wolz
Lucie
L
D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology*; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009840:Oligomycins / Q000494:pharmacology; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D013347:Subcellular Fractions; D014157:Transcription Factors; D014162:Transfection; D019014:fas Receptor / Q000096:biosynthesis* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C116906:BAG4 protein, human; C091732:BCL2-associated athanogene 1 protein; C487979:Bag4 protein, mouse; D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D009840:Oligomycins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014157:Transcription Factors; D019014:fas Receptor; D000255:Adenosine Triphosphate