Article
- The EMBO Journal (2007) 26, 113 - 122
- doi:10.1038/sj.emboj.7601490
Published online: 14 December 2006
Subject Category:
Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase 'Synoviolin'
Satoshi Yamasaki1,a, Naoko Yagishita1,a, Takeshi Sasaki1,a, Minako Nakazawa1,a, Yukihiro Kato1,a, Tadayuki Yamadera1,a, Eunkyung Bae2,a, Sayumi Toriyama1, Rie Ikeda1, Lei Zhang1, Kazuko Fujitani1, Eunkyung Yoo2, Kaneyuki Tsuchimochi1, Tomohiko Ohta3, Natsumi Araya1, Hidetoshi Fujita1, Satoko Aratani1, Katsumi Eguchi4, Setsuro Komiya5, Ikuro Maruyama6, Nobuyo Higashi7, Mitsuru Sato7, Haruki Senoo7, Takahiro Ochi8, Shigeyuki Yokoyama9, Tetsuya Amano1, Jaeseob Kim2, Steffen Gay10, Akiyoshi Fukamizu11, Kusuki Nishioka12, Keiji Tanaka13 and Toshihiro Nakajima1
- Department of Genome Science, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Japan
- GenExl, Inc. Biomedical Research Center, Taejon, South Korea
- Division of Breast and Endocrine Surgery, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Japan
- The First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
- Department of Orthopedic Surgery, Kagoshima University, Faculty of Medicine, Kagoshima, Japan
- Department of Dermatology and Laboratory of Molecular Medicine, Kagoshima University, Faculty of Medicine, Kagoshima, Japan
- Department of Anatomy, Akita University School of Medicine, Akita, Japan
- National Hospital Organization Sagamihara National Hospital, Kanagawa, Japan
- Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan; Protein Research Group, RIKEN Genomic Sciences Center, Yokohama, Japan
- Department of Rheumatology, University Hospital Zürich, Zürich, Switzerland
- Aspect of Functional Genomic Biology, Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
- Rheumatology, Immunology and Genetics Program, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Japan
- Laboratory of Frontier Science, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Correspondence to:
Toshihiro Nakajima, Department of Genome Science, Institute of Medical Science, St Marianna University School of Medicine, 2-16-1 Sugao Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan. Tel.: +81 44 977 8111 (ext. 4111); Fax: +81 44 977 10712; E-mail: nakashit@marianna-u.ac.jp
aThese authors contributed equally to this work
Received 11 April 2006; Accepted 7 November 2006
Abstract
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.
Keywords:
- apoptosis,
- cell growth,
- E3 ubiquitin ligase,
- endoplasmic reticulum-associated degradation,
- rheumatoid arthritis
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