title: Xenopus death receptor-M1 and -M2, new members of the tumor necrosis factor receptor superfamily, trigger apoptotic signaling by differential mechanisms.
abstract: Signaling through the tumor necrosis factor receptor (TNFR) superfamily can lead to apoptosis or promote cell survival, proliferation, and differentiation. A subset of this family, including TNFR1 and Fas, signals cell death via an intracellular death domain and therefore is termed the death receptor (DR) family. In this study, we identified new members of the DR family, designated xDR-M1 and xDR-M2, in Xenopus laevis. The two proteins, which show high homology (71.7% identity), have characteristics of the DR family, that is, three cysteine-rich domains, a transmembrane domain, and a death domain. To elucidate how members of xDR-M subfamily regulate cell death and survival, we examined the intracellular signaling mediated by these receptors in 293T and A6 cells. Overexpression of xDR-M2 induced apoptosis and activated caspase-8, c-Jun N-terminal kinase, and nuclear factor-kappaB, although its death domain to a greater extent than did that of xDR-M1 in 293T cells. A caspase-8 inhibitor potently blocked this apoptosis induced by xDR-M2. In contrast, xDR-M1 showed a greater ability to induce apoptosis through its death domain than did xDR-M2 in A6 cells. Interestingly, a general serine protease inhibitor, but not the caspase-8 inhibitor, blocked the xDR-M1-induced apoptosis. These results imply that activation of caspase-8 or serine protease(s) may be required for the xDR-M2- or xDR-M1-induced apoptosis, respectively. Although xDR-M1 and xDR-M2 are very similar to each other, the difference in their death domains may result in diverse signaling, suggesting distinct roles of xDR-M1 and xDR-M2 in cell death or survival.
authors.affiliation: Department of Biosciences, School of Science, Kitasato University, 1-15-1 Kitasato, Sagamihara 228-8555, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Tamura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Noyama
authors.forename: Yo-Hei
authors.initials: YH
authors.lastname: Ishizawa
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Takamatsu
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Shiba
authors.forename: Michihiko
authors.initials: M
authors.lastname: Ito
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D003545:Cysteine; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017385:Sequence Homology; D015398:Signal Transduction; D014162:Transfection; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis; D019014:fas Receptor / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D029867:Xenopus Proteins; C484516:death receptor M1, Xenopus; C484517:death receptor M2, Xenopus; D019014:fas Receptor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases; D003545:Cysteine