Yamasaki Satoshi, Yagishita Naoko, Sasaki Takeshi, Nakazawa Minako, Kato Yukihiro, Yamadera Tadayuki, Bae Eunkyung, Toriyama Sayumi, Ikeda Rie, Zhang Lei, Fujitani Kazuko, Yoo Eunkyung, Tsuchimochi Kaneyuki, Ohta Tomohiko, Araya Natsumi, Fujita Hidetoshi, Aratani Satoko, Eguchi Katsumi, Komiya Setsuro, Maruyama Ikuro, Higashi Nobuyo, Sato Mitsuru, Senoo Haruki, Ochi Takahiro, Yokoyama Shigeyuki, Amano Tetsuya, Kim Jaeseob, Gay Steffen, Fukamizu Akiyoshi, Nishioka Kusuki, Tanaka Keiji, Nakajima Toshihiro
Department of Genome Science, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Japan.
EMBO J. 2007 Jan 10;26(1):113-22. doi: 10.1038/sj.emboj.7601490. Epub 2006 Dec 14.
Synoviolin, also called HRD1, is an E3 ubiquitin ligase and is implicated in endoplasmic reticulum -associated degradation. In mammals, Synoviolin plays crucial roles in various physiological and pathological processes, including embryogenesis and the pathogenesis of arthropathy. However, little is known about the molecular mechanisms of Synoviolin in these actions. To clarify these issues, we analyzed the profile of protein expression in synoviolin-null cells. Here, we report that Synoviolin targets tumor suppressor gene p53 for ubiquitination. Synoviolin sequestrated and metabolized p53 in the cytoplasm and negatively regulated its cellular level and biological functions, including transcription, cell cycle regulation and apoptosis. Furthermore, these p53 regulatory functions of Synoviolin were irrelevant to other E3 ubiquitin ligases for p53, such as MDM2, Pirh2 and Cop1, which form autoregulatory feedback loops. Our results provide novel insights into p53 signaling mediated by Synoviolin.
滑膜素，也称为HRD1，是一种E3泛素连接酶，参与内质网相关的蛋白质降解过程。在哺乳动物中，滑膜素在各种生理和病理过程中发挥关键作用，包括胚胎发育和关节病的发病机制。然而，关于滑膜素在这些作用中的分子机制知之甚少。为了阐明这些问题，我们分析了滑膜素基因缺失细胞中的蛋白质表达谱。在此，我们报告滑膜素靶向肿瘤抑制基因p53进行泛素化。滑膜素在细胞质中隔离并代谢p53，并对其细胞水平和生物学功能产生负调控，包括转录、细胞周期调控和细胞凋亡。此外，滑膜素对p53的这些调控功能与其他针对p53的E3泛素连接酶无关，如形成自动调节反馈环的MDM2、Pirh2和Cop1。我们的结果为滑膜素介导的p53信号传导提供了新的见解。
