Facilitation of DNA damage-induced apoptosis by endoplasmic reticulum protein mitsugumin23.
Facilitation of DNA damage-induced apoptosis by endoplasmic reticulum protein mitsugumin23.
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DOI：
10.1016/j.bbrc.2010.01.013
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发表时间：
2010-02
影响因子：
3.1
通讯作者：
T. Yamazaki;Nozomi Sasaki;M. Nishi;H. Takeshima
中科院分区：
文献类型：
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作者：
T. Yamazaki;Nozomi Sasaki;M. Nishi;H. Takeshima
内质网（ER）发出依赖于环境的信号，从而介导细胞对各种应激的反应。然而，潜在的分子机制一直是谜。为了更好地理解ER的信号传导能力，我们专注于mitsugumin23（MG23）所扮演的角色，这是一种主要存在于这个细胞器中的蛋白质。MG23在人胚肾293T细胞中的过表达特异性地增强了DNA损伤抗癌药物依托泊苷引发的凋亡。相反，MG23的基因缺失降低了胸腺细胞对DNA损伤诱导的凋亡的敏感性，这一点已通过全身照射实验得到证实。在这种情况下，肿瘤抑制基因p53的诱导减弱MG23敲除胸腺细胞相比，其野生型对应物，与放射抗性升高一致。因此，它表明，MG 23是一个必要的组成部分，ER产生的致命信号挑起后，DNA损伤，指定细胞命运的病理生理条件下。
The endoplasmic reticulum (ER) emanates context-dependent signals, thereby mediating cellular response to a variety of stresses. However, the underlying molecular mechanisms have been enigmatic. To better understand the signaling capacity of the ER, we focused on roles played by mitsugumin23 (MG23), a protein residing predominantly in this organelle. Overexpression of MG23 in human embryonic kidney 293T cells specifically enhanced apoptosis triggered by etoposide, a DNA-damaging anti-cancer drug. Conversely, genetic deletion of MG23 reduced susceptibility of thymocytes to DNA damage-induced apoptosis, which was demonstrated by whole-body irradiation experiments. In this setting, induction of the tumor-suppressor gene p53 was attenuated in MG23-knockout thymocytes as compared with their wild-type counterparts, consistent with the elevated radioresistance. It is therefore suggested that MG23 is an essential component of ER-generated lethal signals provoked upon DNA damage, specifying cell fate under pathophysiological conditions.