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 cysteinerich 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-B, 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-

The adaptor protein TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm

“…While death induced by expression of the death domain of xDR-M2 is blocked by inhibition of caspase-8, death induced by expression of the death domain of xDR-M1 is blocked by serine protease inhibition. 37 Our data indicate that the apoptotic pathway activated by nuclear TRADD does not require caspase-8 or caspase-2. Instead, death is dependent upon caspase-9, which must have an intact catalytic site and be able to form dimers.…”

Tumor necrosis factor–related apoptosis-inducing ligand 1 (TRAIL1) enhances the transition of red blood cells from the larval to adult type during metamorphosis in Xenopus

“…[20][21][22][23] The TR-regulated aspects of metamorphosis include programmed cell death; however, little is known about the intracellular pathway that is involved in the apoptotic signal elicited by the TR-T 3 complex. To investigate whether DR signaling is involved in the metamorphosis of X laevis, we previously isolated and analyzed the death receptor (DR) members xDR-Ms 24 and xTNFR1, and a DR ligand, xTNF-␣. 25 We found that xTNF-␣ attenuates the T 3 -induced apoptosis of a X laevis endothelial cell line, Xlgoo, probably through its receptor, xTNFR1.…”

Developmental cell death during Xenopus metamorphosis involves BID cleavage and caspase 2 and 8 activation

“…Moreover, death receptor ligands could function in a paracrine/autocrine way, making them potential useful tools for the rapid and coordinated elimination of complex tissues (Kavurma and Khachigian, 2003). Two Xenopus death receptors, xDR-M1 and xDR-M2, have been identified recently (Tamura et al, 2004). As xDR-M1 and xDR-M2 have been shown to induce apoptosis by activation of a serine protease(s) and caspase-8, respectively, it will be of great interest to investigate the possible role of xDR-M2 in the metamorphic apoptotic pathway.…”