Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library.
Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library.
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DOI：
10.1126/sciadv.1701383
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发表时间：
2017-10
期刊：
影响因子：
13.6
通讯作者：
Kasim V
中科院分区：
文献类型：
--
作者：
Huang C;Wu S;Ji H;Yan X;Xie Y;Murai S;Zhao H;Miyagishi M;Kasim V
未剪接形式的XBP 1通过抑制MDM 2蛋白的泛素化来稳定MDM 2蛋白，并调节MDM 2/p53轴。细胞周期进程是活细胞中严格控制的基本过程，任何缺陷都与各种异常密切相关。抑癌基因p53/p21轴是控制细胞周期进程的核心通路，然而，其调控机制尚未完全阐明。为了解开这个关键的网络，我们筛选了一个短发夹RNA表达载体文库，并确定了未剪接的X-box结合蛋白1（XBP 1-u）作为p53/p21轴的一个新的和关键的调节因子。具体而言，XBP 1-u通过增强p53泛素化负调控p53/p21轴，这反过来下调p21表达。我们发现，XBP 1-u抑制诱导G 0-G1期阻滞和抑制细胞增殖。我们进一步报道，由于密码子移位，XBP 1-u的羧基末端与其剪接形式（XBP 1-s）不同，通过抑制其自身泛素化，结合并稳定小鼠双微同源物2（MDM 2）蛋白（p53的负调节因子）。同时，XBP-u过表达通过正向调节MDM 2增强肿瘤发生。总之，我们的研究结果表明，XBP 1-u的功能远远超出了仅仅是XBP 1-s的前体，而是参与了基本的生物过程。此外，这项研究提供了关于MDM 2/p53/p21轴调控的新见解。
The unspliced form of XBP1 stabilizes MDM2 protein by inhibiting its ubiquitination and regulates the MDM2/p53 axis. 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 G0-G1 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 regulating MDM2. Together, our findings suggest that XBP1-u functions far beyond being merely 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.
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影响因子：
3.7
作者：
Kasim V;Wu S;Taira K;Miyagishi M
通讯作者：
Miyagishi M
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
8.4
作者：
Dhyani, Anamika;Machado-Neto, Joao A.;Olalla Saad, Sara T.
通讯作者：
Olalla Saad, Sara T.
影响因子：
56.9
作者：
LIOU, HC;BOOTHBY, MR;GLIMCHER, LH
通讯作者：
GLIMCHER, LH
DOI：
10.1146/annurev-pathol-012414-040349
发表时间：
2016-05-23
期刊：
Annual review of pathology
影响因子：
--
作者：
Karni-Schmidt O;Lokshin M;Prives C
通讯作者：
Prives C