Stress-induced alternative splice forms of MDM2 and MDMX modulate the p53-pathway in distinct ways.
Stress-induced alternative splice forms of MDM2 and MDMX modulate the p53-pathway in distinct ways.
复制标题
DOI：
10.1371/journal.pone.0104444
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Chandler DS
中科院分区：
文献类型：
--
作者：
Jacob AG;Singh RK;Comiskey DF Jr;Rouhier MF;Mohammad F;Bebee TW;Chandler DS
MDM2和MDMX是肿瘤抑制蛋白p53的主要负调节因子，对维持细胞内的稳态至关重要。作为对基因毒性应激的反应，在一些癌症类型中，MDM2和MDMX被交替剪接。剪接变异体MDM2-ALT1和MDMX-ALT2缺乏p53结合结构域，不能负向调节p53。然而，它们保留了促进全长MDM蛋白二聚化的RING结构域。与此一致，MDM2- alt1已被证明通过与全长MDM2的相互作用和失活导致p53的稳定。MDM2-ALT1表达对p53通路的影响及其与MDMX相互作用的性质尚不清楚。此外，结构相似的MDMX-ALT2的作用及其对MDM2-MDMX-p53轴的影响还有待阐明。我们在这里展示了MDM2- alt1能够结合全长MDMX和全长MDM2。此外，我们证明MDMX- alt2能够与全长MDMX和MDM2二聚化，并且MDM2- alt1和MDMX- alt2的表达导致p53蛋白及其下游靶点p21的上调。此外，MDM2-ALT1的表达以p53和p21依赖的方式导致细胞周期阻滞在G1期，这与p21水平升高是一致的。最后，我们提供的证据表明，MDM2-ALT1和MDMX-ALT2表达可以激活p53转录靶点的微妙不同亚群，这意味着这些剪接变体可以以独特的方式调节p53肿瘤抑制通路。综上所述，我们的研究表明，应激诱导的替代剪接形式MDM2-ALT1和MDMX-ALT2是p53通路的重要修饰因子，并提供了一种定制p53介导的细胞应激反应的潜在机制。
MDM2 and MDMX are the chief negative regulators of the tumor-suppressor protein p53 and are essential for maintaining homeostasis within the cell. In response to genotoxic stress and also in several cancer types, MDM2 and MDMX are alternatively spliced. The splice variants MDM2-ALT1 and MDMX-ALT2 lack the p53-binding domain and are incapable of negatively regulating p53. However, they retain the RING domain that facilitates dimerization of the full-length MDM proteins. Concordantly, MDM2-ALT1 has been shown to lead to the stabilization of p53 through its interaction with and inactivation of full-length MDM2. The impact of MDM2-ALT1 expression on the p53 pathway and the nature of its interaction with MDMX remain unclear. Also, the role of the architecturally similar MDMX-ALT2 and its influence of the MDM2-MDMX-p53 axis are yet to be elucidated. We show here that MDM2-ALT1 is capable of binding full-length MDMX as well as full-length MDM2. Additionally, we demonstrate that MDMX-ALT2 is able to dimerize with both full-length MDMX and MDM2 and that the expression of MDM2-ALT1 and MDMX-ALT2 leads to the upregulation of p53 protein, and also of its downstream target p21. Moreover, MDM2-ALT1 expression causes cell cycle arrest in the G1 phase in a p53 and p21 dependent manner, which is consistent with the increased levels of p21. Finally we present evidence that MDM2-ALT1 and MDMX-ALT2 expression can activate subtly distinct subsets of p53-transcriptional targets implying that these splice variants can modulate the p53 tumor suppressor pathway in unique ways. In summary, our study shows that the stress-inducible alternative splice forms MDM2-ALT1 and MDMX-ALT2 are important modifiers of the p53 pathway and present a potential mechanism to tailor the p53-mediated cellular stress response.
登录
查看更多内容
浏览p53调节后翻译后修改网络。
影响因子：
9.2
作者：
Gu B;Zhu WG
通讯作者：
Zhu WG
影响因子：
3.7
作者：
Eischen CM;Boyd K
通讯作者：
Boyd K
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
DOI：
10.1073/pnas.94.12.6048
发表时间：
1997-06-10
影响因子：
11.1
作者：
Fiscella, M;Zhang, HL;Appella, E
通讯作者：
Appella, E
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B