Roth Wilfried, Stenner-Liewen Frank, Pawlowski Krzysztof, Godzik Adam, Reed John C
The Burnham Institute, 10901 N Torrey Pines Road, La Jolla, CA 92037, USA.
J Biol Chem. 2002 Mar 1;277(9):7501-8. doi: 10.1074/jbc.M110749200. Epub 2001 Dec 11.
A novel Death Effector Domain-containing protein was identified, DEDD2, which is closest in amino acid sequence homology to death effector domain-containing DNA-binding protein, DEDD. DEDD2 mRNA is expressed widely in adult human tissues with highest levels in liver, kidney, and peripheral blood leukocytes. DEDD2 interacts with FLIP, but not with Fas-associated death domain (FADD) or caspase-8. Overexpression of DEDD2 induces moderate apoptosis and results in substantial sensitization to apoptosis induced by Fas (CD95/APO-1), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L), or FADD. In contrast, Bax- or staurosporine-mediated cell death is not affected by expression of DEDD2. Fluorescence microscopy showed that overexpressed DEDD2 translocates to the nucleus, which is dependent on the presence of a bipartite nuclear localization signal in the DEDD2 protein. Mutagenesis studies revealed that the translocation of the DED of DEDD2 to the nucleus is essential for its pro-apoptotic activity. These findings suggest that DEDD2 is involved in the regulation of nuclear events mediated by the extrinsic apoptosis pathway.
一种新的含死亡效应结构域的蛋白被鉴定出来，即DEDD2，它在氨基酸序列同源性上与含死亡效应结构域的DNA结合蛋白DEDD最为接近。DEDD2 mRNA在成人组织中广泛表达，在肝脏、肾脏和外周血白细胞中表达水平最高。DEDD2与FLIP相互作用，但不与Fas相关死亡结构域（FADD）或半胱天冬酶-8相互作用。DEDD2的过表达诱导中度凋亡，并导致对Fas（CD95/APO-1）、肿瘤坏死因子相关凋亡诱导配体（TRAIL，Apo2L）或FADD诱导的凋亡产生显著的敏感性。相反，Bax或星形孢菌素介导的细胞死亡不受DEDD2表达的影响。荧光显微镜显示，过表达的DEDD2易位至细胞核，这依赖于DEDD2蛋白中双分型核定位信号的存在。诱变研究表明，DEDD2的死亡效应结构域向细胞核的易位对其促凋亡活性至关重要。这些发现表明，DEDD2参与了由外源性凋亡途径介导的核事件的调控。
