2017年10月
Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library
SCIENCE ADVANCES
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- 巻
- 3
- 号
- 10
- 開始ページ
- e1701383
- 終了ページ
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1126/sciadv.1701383
- 出版者・発行元
- AMER ASSOC ADVANCEMENT SCIENCE
Cell cycle progression is a tightly controlled fundamental process in living cells, with any defects being closely linked to various abnormalities. The tumor suppressor p53/p21 axis is a core pathway controlling cell cycle progression; however, its regulatory mechanism has not been fully elucidated. In an effort to unravel this crucial network, we screened a short hairpin RNA expression vector library and identified unspliced X-box binding protein 1 (XBP1-u) as a novel and critical regulator of the p53/p21 axis. Specifically, XBP1-u negatively regulates the p53/p21 axis by enhancing p53 ubiquitination, which in turn down-regulates p21 expression. We show that XBP1-u suppression induces G(0)-G(1) phase arrest and represses cell proliferation. We further report that the carboxyl terminus of XBP1-u, which differs from that of its spliced form (XBP1-s) due to a codon shift, binds and stabilizes mouse double minute homolog 2 (MDM2) protein, a negative regulator of p53, by inhibiting its self-ubiquitination. Concomitantly, XBP-u overexpression enhances tumorigenesis by positively regulatingMDM2. Together, our findings suggest that XBP1-u functions far beyond beingmerely a precursor of XBP1-s and, instead, is involved in fundamental biological processes. Furthermore, this study provides new insights regarding the regulation of the MDM2/p53/p21 axis.
- リンク情報
- ID情報
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- DOI : 10.1126/sciadv.1701383
- ISSN : 2375-2548
- ORCIDのPut Code : 43745314
- Web of Science ID : WOS:000417998700035