Prominent dominant negative effect of a mutant Fas molecule lacking death domain on cell-mediated induction of apoptosis.
Using a panel of transfectant B lymphoma cells expressing varying amounts of the mutant Fas together with the endogenous wild type Fas, semi-quantitative studies on the dominant negative effect of a murine mutant Fas molecule lacking death domain were carried out. In anti-Fas antibody-mediated induction of apoptosis, the mutant molecules exerted significant dominant-negative effect only when their expression level was comparable to or higher than that of wild type molecules, or when exposed to low amounts of the antibody. The inhibitory effect was accompanied by the failure in DISC formation in spite of Fas aggregation. When they were subjected to T cell-mediated Fas-based induction of apoptosis, however, the dominant negative effect was prominent such that the expression of even a small amount of the mutant molecules resulted in significant inhibition. Such a strong inhibitory effect explains the dominant phenotype of this type of mutant Fas molecules in ALPS heterozygous patients and also implies that the physiological effectors for Fas in vivo are cells, i.e., FasL-expressing activated T cells.
Yokota
Aya
A
Department of Immunology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan.
Takeuchi
Emiko
E
Iizuka
Misao
M
Ikegami
Yuko
Y
Takayama
Hajime
H
Shinohara
Nobukata
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D002450:Cell Communication; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein; D005799:Genes, Dominant / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000473:pathology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000502:physiology; D014162:Transfection; D019014:fas Receptor / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
D000911:Antibodies, Monoclonal; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor