FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis.
CD95 (Fas/APO-1) and tumor necrosis factor receptor-1 (TNFR-1) are related molecules that signal apoptosis. Recently, a number of novel binding proteins have been proposed to mediate the signaling of these death receptors. Here we report that an N-terminal truncation of one of these candidate signal transducers, FADD/MORT1, abrogates CD95-induced apoptosis, ceramide generation, and activation of the cell death protease Yama/CPP32. In addition, this dominant-negative derivative of FADD (FADD-DN) blocked TNF-induced apoptosis while not affecting NF- kappaB activation. FADD-DN bound both receptors, and in the case of CD95, it disrupted the assembly of a signaling complex. Taken together, our results functionally establish FADD as the apoptotic trigger of CD95 and TNFR-1.
Chinnaiyan
A M
AM
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Tepper
C G
CG
Seldin
M F
MF
O'Rourke
K
K
Kischkel
F C
FC
Hellbardt
S
S
Krammer
P H
PH
Peter
M E
ME
Dixit
V M
VM
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D017209:Apoptosis; D001943:Breast Neoplasms; D002352:Carrier Proteins / Q000502:physiology*; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000494:pharmacology; D007700:Kinetics; D016393:Lymphoma, B-Cell; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011817:Rabbits / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D002352:Carrier Proteins; D002518:Ceramides; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D007075:Immunoglobulin M; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D019014:fas Receptor