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

TitleA crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response
Authors
Issue Date2012
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ncomms/index.html
Citation
Nature Communications, 2012, v. 3, article no. 836 How to Cite?
AbstractDNA 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. © 2012 Macmillan Publishers Limited. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/183403
ISSN
2015 Impact Factor: 11.329
2015 SCImago Journal Rankings: 6.539
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChau, JFLen_US
dc.contributor.authorJia, Den_US
dc.contributor.authorWang, Zen_US
dc.contributor.authorLiu, Zen_US
dc.contributor.authorHu, Yen_US
dc.contributor.authorZhang, Xen_US
dc.contributor.authorJia, Hen_US
dc.contributor.authorLai, KPen_US
dc.contributor.authorLeong, WFen_US
dc.contributor.authorAu, BJen_US
dc.contributor.authorMishina, Yen_US
dc.contributor.authorChen, YGen_US
dc.contributor.authorBiondi, Cen_US
dc.contributor.authorRobertson, Een_US
dc.contributor.authorXie, Den_US
dc.contributor.authorLiu, Hen_US
dc.contributor.authorHe, Len_US
dc.contributor.authorWang, Xen_US
dc.contributor.authorYu, Qen_US
dc.contributor.authorLi, Ben_US
dc.date.accessioned2013-05-27T07:12:39Z-
dc.date.available2013-05-27T07:12:39Z-
dc.date.issued2012en_US
dc.identifier.citationNature Communications, 2012, v. 3, article no. 836en_US
dc.identifier.issn2041-1723en_US
dc.identifier.urihttp://hdl.handle.net/10722/183403-
dc.description.abstractDNA 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. © 2012 Macmillan Publishers Limited. All rights reserved.en_US
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ncomms/index.htmlen_US
dc.relation.ispartofNature Communicationsen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBone Morphogenetic Proteins - Genetics - Metabolismen_US
dc.subject.meshCell Cycle Proteins - Genetics - Metabolismen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshDna Damageen_US
dc.subject.meshDna-Binding Proteins - Genetics - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred Balb Cen_US
dc.subject.meshMice, Knockouten_US
dc.subject.meshMice, Nudeen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshProtein-Serine-Threonine Kinases - Genetics - Metabolismen_US
dc.subject.meshSignal Transductionen_US
dc.subject.meshSmad1 Protein - Genetics - Metabolismen_US
dc.subject.meshStomach Neoplasms - Genetics - Metabolismen_US
dc.subject.meshTumor Suppressor Protein P53 - Genetics - Metabolismen_US
dc.subject.meshTumor Suppressor Proteins - Genetics - Metabolismen_US
dc.subject.meshUp-Regulationen_US
dc.titleA crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage responseen_US
dc.typeArticleen_US
dc.identifier.emailLai, KP: ballllai@hotmail.comen_US
dc.identifier.authorityLai, KP=rp01753en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/ncomms1832en_US
dc.identifier.pmid22588298-
dc.identifier.scopuseid_2-s2.0-84864295500en_US
dc.identifier.hkuros223757-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84864295500&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume3en_US
dc.identifier.isiWOS:000304611400031-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridChau, JFL=15828893500en_US
dc.identifier.scopusauthoridJia, D=24484433400en_US
dc.identifier.scopusauthoridWang, Z=45461495300en_US
dc.identifier.scopusauthoridLiu, Z=55322102900en_US
dc.identifier.scopusauthoridHu, Y=55501419800en_US
dc.identifier.scopusauthoridZhang, X=55321759400en_US
dc.identifier.scopusauthoridJia, H=55322006600en_US
dc.identifier.scopusauthoridLai, KP=7402135707en_US
dc.identifier.scopusauthoridLeong, WF=55255559900en_US
dc.identifier.scopusauthoridAu, BJ=55194935100en_US
dc.identifier.scopusauthoridMishina, Y=7007002204en_US
dc.identifier.scopusauthoridChen, YG=8451249300en_US
dc.identifier.scopusauthoridBiondi, C=7005315910en_US
dc.identifier.scopusauthoridRobertson, E=35494533600en_US
dc.identifier.scopusauthoridXie, D=7202588196en_US
dc.identifier.scopusauthoridLiu, H=55322101100en_US
dc.identifier.scopusauthoridHe, L=55158160500en_US
dc.identifier.scopusauthoridWang, X=55322027700en_US
dc.identifier.scopusauthoridYu, Q=50562423800en_US
dc.identifier.scopusauthoridLi, B=7410078924en_US

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