DR5 knockout mice are compromised in radiation-induced apoptosis
DR5 knockout mice are compromised in radiation-induced apoptosis
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DOI：
10.1128/mcb.25.5.2000-2013.2005
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发表时间：
2005-03-01
影响因子：
5.3
通讯作者：
El-Deiry, WS
中科院分区：
文献类型：
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作者：
Finnberg, N;Gruber, JJ;El-Deiry, WS
DR 5（也称为TRAIL受体2和KILLER）是肿瘤坏死因子相关凋亡诱导配体（也称为TRAIL和Apo 2配体）的凋亡诱导膜受体。DR 5是p53的转录靶点，其过表达在体外诱导细胞死亡。然而，DR 5的体内生物学仍然在很大程度上未被探索。为了更好地了解DR 5在发育和成人组织中的作用，我们创造了一种缺乏DR 5的基因敲除小鼠。这只小鼠能存活，除胸腺增大外发育正常。我们发现DR 5在发育中的胚胎中不表达，但在发育早期存在于蜕膜和绒毛膜中。表达E1 A的DR 5缺失小鼠胚胎成纤维细胞对TRAIL治疗有抗性，表明DR 5可能是小鼠中TRAIL的主要促凋亡受体。当暴露于电离辐射时，与野生型胸腺、脾、派尔集合淋巴结和脑的白色物质相比，DR 5-nuII组织表现出细胞凋亡量减少。在回肠、结肠和胃中，DR 5缺乏与辐射诱导的细胞死亡的微妙表型相关。这些结果表明，DR 5在胚胎发生和早期发育阶段的作用有限，但在DNA损伤刺激的反应中发挥器官特异性作用。
DR5 (also called TRAIL receptor 2 and KILLER) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called TRAIL and Apo2 ligand). DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro. However, the in vivo biology of DR5 has remained largely unexplored. To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-nuII tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli.