Mdmx promotes genomic instability independent of p53 and Mdm2.
Mdmx promotes genomic instability independent of p53 and Mdm2.
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作者：
致癌基因Mdmx在许多人类恶性肿瘤中过表达，并与Mdm2一起负向调节肿瘤抑制因子p53。然而，已经描述了Mdmx影响基因组稳定性的不依赖于p53的功能，但这种功能尚未得到很好的理解。在目前的研究中，我们确定在评估的13种不同的癌症类型中，6-90%的Mdmx水平升高的患者同时存在p53失活（突变或缺失）。我们发现，Mdmx水平的升高抑制了双链DNA断裂修复，诱导了独立于p53的染色体和染色单体断裂，导致基因组不稳定。Mdmx破坏早期DNA损伤反应信号，如丝氨酸/苏氨酸-谷氨酰胺基序的磷酸化，由ATM激酶介导。此外，我们发现Mdmx与Mre11-Rad50-Nbs1 (MRN) DNA修复复合体的Nbs1相关，这种关联在DNA损伤时增加，并在染色质上被检测到。Mdmx水平升高也以不依赖p53的方式增加细胞转化。出乎意料的是，所有Mdmx介导的表型也发生在缺乏Mdm2的细胞中，并且不依赖于Mdmx的Mdm2结合域（RING）。因此，Mdm2介导的DNA损伤反应抑制导致DNA修复延迟，增加基因组不稳定性和不依赖于p53和Mdm2的转化。我们的研究结果揭示了一种新的不依赖于p53和mdm2的Mdmx的致癌功能，为许多过表达Mdmx的癌症提供了新的见解。
The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor. However, a p53-independent function of Mdmx that impacts genome stability has been described, but this function is not well understood. In the present study, we determined that of the thirteen different cancer types evaluated, 6–90% of those that had elevated levels of Mdmx had concurrent inactivation (mutated or deleted) of p53. We show elevated levels of Mdmx inhibited double-strand DNA break repair and induced chromosome and chromatid breaks independent of p53, leading to genome instability. Mdmx impaired early DNA damage response signaling, such as phosphorylation of the serine/threonine-glutamine motif, mediated by the ATM kinase. Moreover, we identified Mdmx associated with Nbs1 of the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and this association increased upon DNA damage and was detected at chromatin. Elevated Mdmx levels also increased cellular transformation in a p53-independent manner. Unexpectedly, all Mdmx-mediated phenotypes also occurred in cells lacking Mdm2 and were independent of the Mdm2-binding domain (RING) of Mdmx. Therefore, Mdmx-mediated inhibition of the DNA damage response resulted in delayed DNA repair and increased genome instability and transformation independent of p53 and Mdm2. Our results reveal a novel p53- and Mdm2-independent oncogenic function of Mdmx that provides new insight into the many cancers that overexpress Mdmx.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.4161/cc.7.19.6797
发表时间：
2008-10
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Matijasevic Z;Krzywicka-Racka A;Sluder G;Jones SN
通讯作者：
Jones SN
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：
6.5
作者：
Leventaki, Vasiliki;Rodic, Vladimir;Miles, Rodney R.
通讯作者：
Miles, Rodney R.