MDMX under stress: the MDMX-MDM2 complex as stress signals hub.
MDMX under stress: the MDMX-MDM2 complex as stress signals hub.
复制标题
DOI：
10.21037/tcr.2016.12.18
复制
发表时间：
2016-12
影响因子：
0.9
通讯作者：
Yuan ZM
中科院分区：
文献类型：
--
作者：
de Polo A;Vivekanandan V;Little JB;Yuan ZM
肿瘤抑制基因P53在维持细胞内环境稳定方面发挥着核心作用。在DNA损伤或致癌应激等各种应激信号作用下，P53被迅速激活，以防止和修复可能威胁基因组稳定性的损伤。P53的两个主要负调控因子是MDM2和MDMX，这两个同源蛋白控制着P53的活性和周转，从而使其在正常的细胞周期中处于受控状态。在细胞应激的情况下，它们必须被抑制，以便将P53从抑制中释放出来，并允许其激活。作为p53的重要上游调节因子，MDMX-MDM2复合体整合了多种信号通路，调节P53对细胞内稳态的干扰。鉴于其在正常情况下主要分布在细胞质中，我们假设MDMX而不是MDM2是针对MDMX-MDM2复合体的信号信号的第一个接收者，目的是调控p53。在这篇综述中，我们综述了MDMX的磷酸化位点，这些位点影响MDMX的降解、泛素化、细胞内定位以及与MDM2和P53的相互作用，最终调节P53的稳定性和活性。还简要讨论了MDMX在应对主要类型的细胞应激中的作用，以及MDMX-MDM2复合体作为恢复P53活性的治疗靶点的潜力。
The tumor suppressor p53 plays a central role in safeguarding cellular homeostasis. Upon various types of stress signals such as DNA damage or oncogenic stress, p53 is promptly activated to prevent and repair damages that can threaten the genome stability. The two major negative regulators of p53 are MDM2 and MDMX, two homolog proteins that control p53 activity and turnover, hence keeping it in check during normal cell cycling. In the event of cellular stress, they have to be inhibited in order to relieve p53 from their suppression and allow its activation. As the essential upstream modulator of p53, the MDMX-MDM2 complex integrates multiple signaling pathways regulating p53 response to perturbations of cellular homeostasis. Given its predominantly cytoplasmic localization in normal conditions, we hypothesize that MDMX, rather than MDM2, is the first recipient of signaling cues directed towards the MDMX-MDM2 complex and aimed at modulating p53. In this review we give a synthetic overview of the phosphorylation sites of MDMX that are known to affect its degradation, ubiquitination, intracellular localization and interaction with MDM2 and p53, ultimately modulating the stability and activity of p53. The role of MDMX in response to the main types of cellular stress is also briefly discussed, along with the potential of the MDMX-MDM2 complex as therapeutic target to restore p53 activity.
登录
查看更多内容
影响因子：
3.7
作者：
Bista M;Smithson D;Pecak A;Salinas G;Pustelny K;Min J;Pirog A;Finch K;Zdzalik M;Waddell B;Wladyka B;Kedracka-Krok S;Dyer MA;Dubin G;Guy RK
通讯作者：
Guy RK
影响因子：
5.3
作者：
Gilkes, Daniele M.;Pan, Yu;Chen, Jiandong
通讯作者：
Chen, Jiandong
影响因子：
8
作者：
de Lange, J.;Ly, L. V.;Jochemsen, A. G.
通讯作者：
Jochemsen, A. G.
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