A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response
A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response
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骨形态发生蛋白 Smad1 信号在 DNA 损伤反应中的关键作用
DOI：
10.1038/ncomms1832
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发表时间：
2012-05-01
影响因子：
16.6
通讯作者：
Li, Baojie
中科院分区：
文献类型：
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作者：
Chau, Jenny Fung Ling;Jia, Deyong;Li, Baojie
DNA损伤和引发的细胞反应是肿瘤发生和衰老的病因学基础。然而，这种反应如何整合来自细胞环境线索的输入仍然没有得到充分的研究。在这里，我们报告的BMP-Smad 1途径，这是胚胎发育和组织稳态所必需的，在DNA损伤反应和肿瘤发生中具有重要作用。在遗传毒性胁迫下，Atm磷酸化S239细胞核中BMP激活的Smad 1，破坏Smad 1与蛋白磷酸酶PPM 1A的相互作用，导致Smad 1的激活和上调。然后Smad 1与p53相互作用，抑制Mdm 2介导的p53泛素化和降解，以调节细胞增殖和存活。在食管癌和胃癌中分别检测到Smad 1 S239磷酸化增强和Smad 1突变引起的S239置换。这些发现表明BMP-Smad 1信号通过Atm-p53途径参与DNA损伤反应，从而提供了BMP-Smad 1功能丧失导致肿瘤发生的分子机制，例如，青少年息肉病和Cowden综合征。
DNA damage and the elicited cellular response underlie the etiology of tumorigenesis and ageing. Yet, how this response integrates inputs from cells' environmental cues remains underexplored. Here we report that the BMP-Smad1 pathway, which is essential for embryonic development and tissue homeostasis, has an important role in the DNA damage response and oncogenesis. On genotoxic stress, Atm phosphorylates BMPs-activated Smad1 in the nucleus on S239, which disrupts Smad1 interaction with protein phosphatase PPM1A, leading to enhanced activation and upregulation of Smad1. Smad1 then interacts with p53 and inhibits Mdm2-mediated p53 ubiquitination and degradation to regulate cell proliferation and survival. Enhanced Smad1 S239 phosphorylation, andSmad1mutations causing S239 substitution were detected in oesophageal and gastric cancer samples, respectively. These findings suggest that BMP-Smad1 signalling participates in the DNA damage response via the Atm-p53 pathway, thus providing a molecular mechanism whereby BMP-Smad1 loss-of-function leads to tumorigenesis, for example, juvenile polyposis and Cowden syndromes.