Stegh A H, Schickling O, Ehret A, Scaffidi C, Peterhänsel C, Hofmann T G, Grummt I, Krammer P H, Peter M E
Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
EMBO J. 1998 Oct 15;17(20):5974-86. doi: 10.1093/emboj/17.20.5974.
The CD95 signaling pathway comprises proteins that contain one or two death effector domains (DED), such as FADD/Mort1 or caspase-8. Here we describe a novel 37 kDa protein, DEDD, that contains an N-terminal DED. DEDD is highly conserved between human and mouse (98. 7% identity) and is ubiquitously expressed. Overexpression of DEDD in 293T cells induced weak apoptosis, mainly through its DED by which it interacts with FADD and caspase-8. Endogenous DEDD was found in the cytoplasm and translocated into the nucleus upon stimulation of CD95. Immunocytological studies revealed that overexpressed DEDD directly translocated into the nucleus, where it co-localizes in the nucleolus with UBF, a basal factor required for RNA polymerase I transcription. Consistent with its nuclear localization, DEDD contains two nuclear localization signals and the C-terminal part shares sequence homology with histones. Recombinant DEDD binds to both DNA and reconstituted mononucleosomes and inhibits transcription in a reconstituted in vitro system. The results suggest that DEDD is a final target of a chain of events by which the CD95-induced apoptotic signal is transferred into the nucleolus to shut off cellular biosynthetic activities.
CD95信号通路包含含有一个或两个死亡效应结构域（DED）的蛋白质，如FADD/Mort1或半胱天冬酶-8。在此，我们描述了一种新型的37 kDa蛋白质DEDD，它含有一个N端DED。DEDD在人和小鼠之间高度保守（同一性为98.7%），且广泛表达。在293T细胞中过表达DEDD会诱导微弱的细胞凋亡，主要是通过其DED与FADD和半胱天冬酶-8相互作用。内源性DEDD存在于细胞质中，在CD95受到刺激时会转移到细胞核中。免疫细胞化学研究表明，过表达的DEDD直接转移到细胞核中，在那里它与UBF共定位于核仁，UBF是RNA聚合酶I转录所需的一种基础因子。与其核定位一致，DEDD含有两个核定位信号，并且C端部分与组蛋白具有序列同源性。重组DEDD能与DNA和重组单核小体结合，并在重组体外系统中抑制转录。结果表明，DEDD是一系列事件的最终靶点，通过这些事件，CD95诱导的凋亡信号被传递到核仁以关闭细胞的生物合成活动。
