Increased radioresistance and accelerated B cell lymphomas in mice with Mdmx mutations that prevent modifications by DNA-damage-activated kinases.
Increased radioresistance and accelerated B cell lymphomas in mice with Mdmx mutations that prevent modifications by DNA-damage-activated kinases.
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DOI：
10.1016/j.ccr.2009.05.008
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发表时间：
2009-07-07
期刊：
影响因子：
50.3
通讯作者：
Wahl GM
中科院分区：
文献类型：
--
作者：
Wang YV;Leblanc M;Wade M;Jochemsen AG;Wahl GM
Mdmx是p53通路的关键负调节剂，在某些组织中具有化学计量限制。DNA损伤后Mdmx的翻译后修饰和降解被认为是p53激活的关键。我们在体内测试了这个模型，其中保留了关键的化学计量关系。我们产生了一个Mdmx突变小鼠，其中三个保守的丝氨酸（S341，S367，S402）的DNA损伤激活激酶靶向丙氨酸取代，以调查这些残基的修饰是否是重要的Mdmx降解和p53激活。突变小鼠对辐射具有显著的抵抗力，并且对Myc诱导的淋巴瘤形成非常敏感。这些数据表明，Mdmx下调是至关重要的有效p53介导的辐射反应和肿瘤抑制体内。P53功能对其负调节因子Mdm 2和Mdmx的水平敏感。细胞培养研究已经表明Mdm 2和Mdmx中的翻译后修饰对于p53激活的重要性，但是这还没有在体内进行严格的测试。这项工作表明，DNA损伤和活化的c-Myc都需要在损伤激酶ATM和Chk 2靶向的残基中磷酸化Mdmx，以实现强大的p53活化。阻止Mdmx翻译后修饰稳定了这种负调节因子，这减轻了p53激活，并可能使c-Myc能够驱动具有缺陷基因组的肿瘤细胞进入体内循环。这些数据还强调了Mdmx作为潜在治疗靶点的相关性。
Mdmx is a critical negative regulator of the p53 pathway that is stoichiometrically limiting in some tissues. Post-translational modification and degradation of Mdmx after DNA damage have been proposed to be essential for p53 activation. We tested this model in vivo, where critical stoichiometric relationships are preserved. We generated an Mdmx mutant mouse in which three conserved serines (S341, S367, S402) targeted by DNA damage-activated kinases were replaced by alanines to investigate whether modifications of these residues are important for Mdmx degradation and p53 activation. The mutant mice were remarkably resistant to radiation, and very susceptible to Myc-induced lymphomagenesis. These data demonstrate that Mdmx down-regulation is crucial for effective p53-mediated radiation responses and tumor suppression in vivo. P53 function is sensitive to the levels of its negative regulators, Mdm2 and Mdmx. Cell culture studies have suggested the importance of post-translational modifications in Mdm2 and Mdmx for p53 activation, but this has not been rigorously tested in vivo. This work shows that DNA damage and activated c-Myc both require phosphorylation of Mdmx in residues targeted by the damage kinases ATM and Chk2 for robust p53 activation. Preventing Mdmx post-translational modification stabilizes this negative regulator, which mitigates p53 activation, and presumably enables c-Myc to drive tumor cells with defective genomes into cycle in vivo. The data also stress the relevance of Mdmx as a potential therapeutic target.
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