Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Biochem Biophys Res Commun. 2010 Feb 5;392(2):196-200. doi: 10.1016/j.bbrc.2010.01.013. Epub 2010 Jan 12.
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.
内质网（ER）发出与上下文相关的信号，从而介导细胞对各种应激的反应。然而，其潜在的分子机制一直是个谜。为了更好地理解 ER 的信号转导能力，我们专注于驻留在该细胞器中的蛋白 mitsugumin23（MG23）所起的作用。在人胚肾 293T 细胞中过表达 MG23 特异性增强了依托泊苷（一种破坏 DNA 的抗癌药物）触发的细胞凋亡。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，这一点通过全身照射实验得到了证明。在这种情况下，与野生型相比，MG23 敲除的胸腺细胞中肿瘤抑制基因 p53 的诱导减弱，与放射抗性的提高一致。因此，MG23 是 ER 在 DNA 损伤时产生的致命信号的必需组成部分，决定了病理生理条件下的细胞命运。
