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Article: HOXB5 cooperates with NKX2-1 in the transcription of human RET

TitleHOXB5 cooperates with NKX2-1 in the transcription of human RET
Authors
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
Plos One, 2011, v. 6 n. 6 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/135531
ISSN
2014 Impact Factor: 3.234
2014 SCImago Journal Rankings: 1.300
PubMed Central ID
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorZhu, Jen_HK
dc.contributor.authorGarciaBarcelo, MMen_HK
dc.contributor.authorTam, PKHen_HK
dc.contributor.authorLui, VCHen_HK
dc.date.accessioned2011-07-27T01:36:35Z-
dc.date.available2011-07-27T01:36:35Z-
dc.date.issued2011en_HK
dc.identifier.citationPlos One, 2011, v. 6 n. 6en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/135531-
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.en_HK
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_HK
dc.relation.ispartofPLoS ONEen_HK
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 RETen_HK
dc.typeArticleen_HK
dc.identifier.emailGarciaBarcelo, MM: mmgarcia@hkucc.hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hkucc.hku.hken_HK
dc.identifier.emailLui, VCH: vchlui@hkucc.hku.hken_HK
dc.identifier.authorityGarciaBarcelo, MM=rp00445en_HK
dc.identifier.authorityTam, PKH=rp00060en_HK
dc.identifier.authorityLui, VCH=rp00363en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0020815en_HK
dc.identifier.pmid21677782-
dc.identifier.pmcidPMC3108997-
dc.identifier.scopuseid_2-s2.0-79958046096en_HK
dc.identifier.hkuros187594en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79958046096&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume6en_HK
dc.identifier.issue6en_HK
dc.identifier.spagee20815en_US
dc.identifier.epagee20815en_US
dc.identifier.eissn1932-6203-
dc.identifier.isiWOS:000291355500045-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridZhu, J=7405690800en_HK
dc.identifier.scopusauthoridGarciaBarcelo, MM=6701767303en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK
dc.identifier.scopusauthoridLui, VCH=7004231344en_HK

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