p53 dynamics vary between tissues and are linked with radiation sensitivity.
p53 dynamics vary between tissues and are linked with radiation sensitivity.
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DOI：
10.1038/s41467-021-21145-z
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发表时间：
2021-02-09
影响因子：
16.6
通讯作者：
Lahav G
中科院分区：
文献类型：
--
作者：
Stewart-Ornstein J;Iwamoto Y;Miller MA;Prytyskach MA;Ferretti S;Holzer P;Kallen J;Furet P;Jambhekar A;Forrester WC;Weissleder R;Lahav G
不同组织对辐射的敏感性差别很大。转录因子p53介导对辐射的反应；然而，p53蛋白的丰度与组织间放射敏感性的程度没有很好的相关性。鉴于最近的研究表明，p53的时间动态影响培养细胞在辐照反应中的命运，我们开始确定p53的动态行为及其对体内辐射敏感性的影响。我们发现放射敏感组织在放射后表现出持续的p53信号传导，而更耐药的组织则表现出短暂的p53激活。使用抑制Mdm2的小分子（NMI801）维持p53， Mdm2是p53的负调节因子，降低细胞培养的活力并抑制肿瘤生长。我们的工作提出了一种控制辐射敏感性的机制，并提出了改变p53动态以增强肿瘤清除的工具。类似的方法可以用来增强对癌细胞的杀伤，或者在基因毒性治疗后降低正常组织的毒性。P53介导对辐照的反应，然而，P53水平相似的组织具有不同的辐射敏感性。在这里，作者表明放射后这些组织中的体内p53动态变化，使用Mdm2抑制剂维持p53活性可增强放射敏感性。
Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies. p53 mediates the response to irradiation, however, tissues with similar levels of p53 have different radiation sensitivities. Here, the authors show that the in vivo p53 dynamics varies in these tissues after radiation, and the use of Mdm2 inhibitor to sustain p53 activity enhances radiosensitivity.
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影响因子：
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