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Article: HOXB5 cooperates with NKX2-1 in the transcription of human RET
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TitleHOXB5 cooperates with NKX2-1 in the transcription of human RET
 
AuthorsZhu, J1
GarciaBarcelo, MM1
Tam, PKH1
Lui, VCH1
 
Issue Date2011
 
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
CitationPlos One, 2011, v. 6 n. 6 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0020815
 
AbstractThe enteric nervous system (ENS) regulates peristaltic movement of the gut, and abnormal ENS causes Hirschsprung's disease (HSCR) in newborns. HSCR is a congenital complex genetic disorder characterised by a lack of enteric ganglia along a variable length of the intestine. The receptor tyrosine kinase gene (RET) is the major HSCR gene and its expression is crucial for ENS development. We have previously reported that (i) HOXB5 transcription factor mediates RET expression, and (ii) mouse with defective HOXB5 activity develop HSCR phenotype. In this study, we (i) elucidate the underlying mechanisms that HOXB5 mediate RET expression, and (ii) examine the interactions between HOXB5 and other transcription factors implicated in RET expression. We show that human HOXB5 binds to the promoter region 5′ upstream of the binding site of NKX2-1 and regulates RET expression. HOXB5 and NKX2-1 form a protein complex and mediate RET expression in a synergistic manner. HSCR associated SNPs at the NKX2-1 binding site (-5G>A rs10900296; -1A>C rs10900297), which reduce NKX2-1 binding, abolish the synergistic trans-activation of RET by HOXB5 and NKX2-1. In contrast to the synergistic activation of RET with NKX2-1, HOXB5 cooperates in an additive manner with SOX10, PAX3 and PHOX2B in trans-activation of RET promoter. Taken together, our data suggests that HOXB5 in coordination with other transcription factors mediates RET expression. Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype. © 2011 Zhu et al.
 
ISSN1932-6203
2012 Impact Factor: 3.73
2012 SCImago Journal Rankings: 1.512
 
DOIhttp://dx.doi.org/10.1371/journal.pone.0020815
 
PubMed Central IDPMC3108997
 
ISI Accession Number IDWOS:000291355500045
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU7713/08M
HKU7654/07M
University of Hong Kong200811159088
Funding Information:

This work was supported by research grants from the Hong Kong Research Grants Council (HKU7713/08M and HKU7654/07M to VCHL and MMGB respectively) and the University of Hong Kong Seed Funding Programme for Basic Research (200811159088) to VCHL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorZhu, J
 
dc.contributor.authorGarciaBarcelo, MM
 
dc.contributor.authorTam, PKH
 
dc.contributor.authorLui, VCH
 
dc.date.accessioned2011-07-27T01:36:35Z
 
dc.date.available2011-07-27T01:36:35Z
 
dc.date.issued2011
 
dc.description.abstractThe enteric nervous system (ENS) regulates peristaltic movement of the gut, and abnormal ENS causes Hirschsprung's disease (HSCR) in newborns. HSCR is a congenital complex genetic disorder characterised by a lack of enteric ganglia along a variable length of the intestine. The receptor tyrosine kinase gene (RET) is the major HSCR gene and its expression is crucial for ENS development. We have previously reported that (i) HOXB5 transcription factor mediates RET expression, and (ii) mouse with defective HOXB5 activity develop HSCR phenotype. In this study, we (i) elucidate the underlying mechanisms that HOXB5 mediate RET expression, and (ii) examine the interactions between HOXB5 and other transcription factors implicated in RET expression. We show that human HOXB5 binds to the promoter region 5′ upstream of the binding site of NKX2-1 and regulates RET expression. HOXB5 and NKX2-1 form a protein complex and mediate RET expression in a synergistic manner. HSCR associated SNPs at the NKX2-1 binding site (-5G>A rs10900296; -1A>C rs10900297), which reduce NKX2-1 binding, abolish the synergistic trans-activation of RET by HOXB5 and NKX2-1. In contrast to the synergistic activation of RET with NKX2-1, HOXB5 cooperates in an additive manner with SOX10, PAX3 and PHOX2B in trans-activation of RET promoter. Taken together, our data suggests that HOXB5 in coordination with other transcription factors mediates RET expression. Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype. © 2011 Zhu et al.
 
dc.description.naturepublished_or_final_version
 
dc.identifier.citationPlos One, 2011, v. 6 n. 6 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0020815
 
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0020815
 
dc.identifier.eissn1932-6203
 
dc.identifier.epagee20815
 
dc.identifier.hkuros187594
 
dc.identifier.isiWOS:000291355500045
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU7713/08M
HKU7654/07M
University of Hong Kong200811159088
Funding Information:

This work was supported by research grants from the Hong Kong Research Grants Council (HKU7713/08M and HKU7654/07M to VCHL and MMGB respectively) and the University of Hong Kong Seed Funding Programme for Basic Research (200811159088) to VCHL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

 
dc.identifier.issn1932-6203
2012 Impact Factor: 3.73
2012 SCImago Journal Rankings: 1.512
 
dc.identifier.issue6
 
dc.identifier.pmcidPMC3108997
 
dc.identifier.pmid21677782
 
dc.identifier.scopuseid_2-s2.0-79958046096
 
dc.identifier.spagee20815
 
dc.identifier.urihttp://hdl.handle.net/10722/135531
 
dc.identifier.volume6
 
dc.languageeng
 
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
dc.publisher.placeUnited States
 
dc.relation.ispartofPLoS ONE
 
dc.relation.referencesReferences in Scopus
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subject.meshHomeodomain Proteins - genetics - metabolism
 
dc.subject.meshNuclear Proteins - genetics - metabolism
 
dc.subject.meshProto-Oncogene Proteins c-ret - genetics - metabolism
 
dc.subject.meshTranscription Factors - genetics - metabolism
 
dc.subject.meshTranscription, Genetic
 
dc.titleHOXB5 cooperates with NKX2-1 in the transcription of human RET
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine