Author
Listed:
- Jenny Fung Ling Chau
(The Institute of Molecular and Cell Biology
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University)
- Deyong Jia
(Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University)
- Zhongfeng Wang
(Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University)
- Zhi Liu
(The Institute of Molecular and Cell Biology)
- Yuanyu Hu
(The Institute of Molecular and Cell Biology)
- Xin Zhang
(Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University)
- Hao Jia
(Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University)
- Keng Po Lai
(The Institute of Molecular and Cell Biology)
- Wai Fook Leong
(The Institute of Molecular and Cell Biology)
- Bi Jin Au
(The Institute of Molecular and Cell Biology)
- Yuji Mishina
(School of Dentistry, University of Michigan)
- Ye-Guang Chen
(Tsinghua University)
- Christine Biondi
(Sir William Dunn School of Pathology, University of Oxford)
- Elizabeth Robertson
(Sir William Dunn School of Pathology, University of Oxford)
- Dong Xie
(Institutes for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)
- Huijuan Liu
(Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University)
- Lin He
(Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University)
- Xueying Wang
(National University of Singapore)
- Qiang Yu
(Genome Institute of Singapore)
- Baojie Li
(Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University)
Abstract
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, and Smad1 mutations 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.
Suggested Citation
Jenny Fung Ling Chau & Deyong Jia & Zhongfeng Wang & Zhi Liu & Yuanyu Hu & Xin Zhang & Hao Jia & Keng Po Lai & Wai Fook Leong & Bi Jin Au & Yuji Mishina & Ye-Guang Chen & Christine Biondi & Elizabeth , 2012.
"A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response,"
Nature Communications, Nature, vol. 3(1), pages 1-11, January.
Handle:
RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1832
DOI: 10.1038/ncomms1832
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