A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

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 Robertson; Dong Xie; Huijuan Liu; Lin He; Xueying Wang; Qiang Yu; Baojie Li

doi:10.1038/ncomms1832

A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

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 Robertson
, Dong Xie
, Huijuan Liu
, Lin He
, Xueying Wang
, Qiang Yu
, Baojie Li

Applied Science

Research output: Contribution to journal › Article › peer-review

44 Citations (Scopus)

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.

Original language	English
Article number	836
Number of pages	11
Journal	Nature Communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms1832 https://doi.org/10.1038/ncomms1832
Publication status	Published - May 2012

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

Cite this

Chau, J. F. L., Jia, D., Wang, Z., Liu, Z., Hu, Y., Zhang, X., Jia, H., Lai, K. P., Leong, W. F., Au, B. J., Mishina, Y., Chen, Y.-G., Biondi, C., Robertson, E., Xie, D., Liu, H., He, L., Wang, X., Yu, Q., & Li, B. (2012). A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response. Nature Communications, 3, Article 836. https://doi.org/10.1038/ncomms1832, https://doi.org/10.1038/ncomms1832

@article{eaaa4894af594c87930847aff0f1e110,

title = "A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response",

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.",

author = "Chau, \{Jenny Fung Ling\} and Deyong Jia and Zhongfeng Wang and Zhi Liu and Yuanyu Hu and Xin Zhang and Hao Jia and Lai, \{Keng Po\} and Leong, \{Wai Fook\} and Au, \{Bi Jin\} and Yuji Mishina and Ye-Guang Chen and Christine Biondi and Elizabeth Robertson and Dong Xie and Huijuan Liu and Lin He and Xueying Wang and Qiang Yu and Baojie Li",

year = "2012",

month = may,

doi = "10.1038/ncomms1832",

language = "English",

volume = "3",

}

Chau, JFL, Jia, D, Wang, Z, Liu, Z, Hu, Y, Zhang, X, Jia, H, Lai, KP, Leong, WF, Au, BJ, Mishina, Y, Chen, Y-G, Biondi, C, Robertson, E, Xie, D, Liu, H, He, L, Wang, X, Yu, Q & Li, B 2012, 'A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response', Nature Communications, vol. 3, 836. https://doi.org/10.1038/ncomms1832, https://doi.org/10.1038/ncomms1832

TY - JOUR

T1 - A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

AU - Chau, Jenny Fung Ling

AU - Jia, Deyong

AU - Wang, Zhongfeng

AU - Liu, Zhi

AU - Hu, Yuanyu

AU - Zhang, Xin

AU - Jia, Hao

AU - Lai, Keng Po

AU - Leong, Wai Fook

AU - Au, Bi Jin

AU - Mishina, Yuji

AU - Chen, Ye-Guang

AU - Biondi, Christine

AU - Robertson, Elizabeth

AU - Xie, Dong

AU - Liu, Huijuan

AU - He, Lin

AU - Wang, Xueying

AU - Yu, Qiang

AU - Li, Baojie

PY - 2012/5

Y1 - 2012/5

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84864295500

U2 - 10.1038/ncomms1832

DO - 10.1038/ncomms1832

M3 - Article

C2 - 22588298

VL - 3

JO - Nature Communications

JF - Nature Communications

M1 - 836

ER -

A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this