The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2).
The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2).
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DOI：
10.18632/oncotarget.22320
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发表时间：
2017-11-28
期刊：
影响因子：
--
通讯作者：
Mayo LD
中科院分区：
文献类型：
--
作者：
Hauck PM;Wolf ER;Olivos DJ 3rd;McAtarsney CP;Mayo LD
小鼠双微体2（Mdm 2）和MdmX二聚化响应于低水平的遗传毒性应激，以在泛素化复合物中发挥作用，这是p53不稳定的信号。在生长条件下，Mdm 2作为neddylating连接酶发挥作用，但MdmX参与这一过程的重要性和程度在很大程度上是未知的。在这里，我们表明，当Mdm 2作为neddylating酶的功能，MdmX是稳定的。此外，我们证明，在生长条件下，MdmX增强了Mdm 2对p53的neddylation活性，并且是neddylation本身的底物。重要的是，MCF-7乳腺癌细胞中MdmX敲低导致neddylated p53减少，表明MdmX对Mdm 2介导的neddylation很重要。支持这一发现的是，在瞬时测定或p53/MdmX-/- MEFs中缺乏MdmX分别导致p53的neddylation减少或改变;因此，MdmX是Mdm 2介导的neddylating复合物的关键组分。c-Src是该Mdm 2-MdmX neddylating途径的上游激活剂，并且Src信号传导的丧失导致MdmX的不稳定，这依赖于MdmX的RING（真正有趣的新基因）结构域。用neddylation小分子抑制剂MLN 4924处理可导致共济失调毛细血管扩张突变型（ATM）激活。ATM磷酸化Mdm 2，将Mdm 2转化为泛素化酶，导致MdmX的不稳定。这些数据显示了不同的信号通路如何参与neddylating或泛素化活动并影响Mdm 2-MdmX轴。
Mouse double minute 2 (Mdm2) and MdmX dimerize in response to low levels of genotoxic stress to function in a ubiquitinating complex, which signals for destabilization of p53. Under growth conditions, Mdm2 functions as a neddylating ligase, but the importance and extent of MdmX involvement in this process are largely unknown. Here we show that when Mdm2 functions as a neddylating enzyme, MdmX is stabilized. Furthermore, we demonstrate that under growth conditions, MdmX enhances the neddylation activity of Mdm2 on p53 and is a substrate for neddylation itself. Importantly, MdmX knockdown in MCF-7 breast cancer cells resulted in diminished neddylated p53, suggesting that MdmX is important for Mdm2-mediated neddylation. Supporting this finding, the lack of MdmX in transient assays or in p53/MdmX-/- MEFs results in decreased or altered neddylation of p53 respectively; therefore, MdmX is a critical component of the Mdm2-mediated neddylating complex. c-Src is the upstream activator of this Mdm2-MdmX neddylating pathway and loss of Src signaling leads to the destabilization of MdmX that is dependent on the RING (Really Interesting New Gene) domain of MdmX. Treatment with a small molecule inhibitor of neddylation, MLN4924, results in the activation of Ataxia Telangiectasia Mutated (ATM). ATM phosphorylates Mdm2, converting Mdm2 to a ubiquitinating enzyme which leads to the destabilization of MdmX. These data show how distinct signaling pathways engage neddylating or ubiquitinating activities and impact the Mdm2-MdmX axis.
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影响因子：
4.8
作者：
Jackson, Mark W.;Patt, Linnea E.;Mayo, Lindsey D.
通讯作者：
Mayo, Lindsey D.
影响因子：
8
作者：
Mackintosh, C.;Garcia-Dominguez, D. J.;de Alava, E.
通讯作者：
de Alava, E.
影响因子：
64.8
作者：
Laurie, Nikia A.;Donovan, Stacy L.;Dyer, Michael A.
通讯作者：
Dyer, Michael A.
p53 抑制剂 MDM2/MDMX 复合物是控制体内 p53 活性所必需的
DOI：
10.1073/pnas.1102309108
发表时间：
2011-07-19
影响因子：
11.1
作者：
Huang, Lei;Yan, Zheng;Yuan, Zhi-Min
通讯作者：
Yuan, Zhi-Min
影响因子：
82.9
作者：
Gembarska, Agnieszka;Luciani, Flavie;Fedele, Clare;Russell, Elisabeth A.;Dewaele, Michael;Villar, Stephanie;Zwolinska, Aleksandra;Haupt, Sue;de Lange, Job;Yip, Dana;Goydos, James;Haigh, Jody J.;Haupt, Ygal;Larue, Lionel;Jochemsen, Aart;Shi, Hubing;Moriceau, Gatien;Lo, Roger S.;Ghanem, Ghanem;Shackleton, Mark;Bernal, Federico;Marine, Jean-Christophe
通讯作者：
Marine, Jean-Christophe