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rdf:type |
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lifeskim:mentions |
umls-concept:C0018787,
umls-concept:C0178555,
umls-concept:C0205314,
umls-concept:C0679622,
umls-concept:C0680730,
umls-concept:C1148554,
umls-concept:C1413784,
umls-concept:C1416962,
umls-concept:C1519818,
umls-concept:C1521761,
umls-concept:C1709100,
umls-concept:C1879547
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pubmed:issue |
11
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pubmed:dateCreated |
2004-3-8
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pubmed:abstractText |
The mammalian homologue of Drosophila tinman, Nkx2-5, plays an early role in regulating cardiac genes and morphogenesis. Bone morphogenetic proteins (BMPs), members of the transforming growth factor (TGF)-beta family of signaling molecules, are involved in numerous developmental processes. BMP signaling is crucial in the regulation of Nkx2-5 expression and specification of the cardiac lineage. Constitutively active BMP type I receptor or the downstream pathway components and DNA-binding transcription factors, Smad1/4 directly activated Nkx2-5 gene transcription. We identified and characterized a novel upstream Nkx2-5 enhancer, composed of clustered repeats of Smad and GATA DNA binding sites. This composite Nkx2-5 enhancer was a direct target of BMP signaling via cooperative interactions between the downstream transducers Smad1/4 and GATA-4. In mammalian two hybrid assays, Smad factors recruited the hybrid gene GATA4-VP16 to strongly drive transcription of a reporter gene containing multimerized Smad binding sites These cofactors interacted through the second zinc finger and adjacent basic domain of GATA-4 and the N-terminal domain of Smads. Smad4 and GATA4 were also found to bind in vivo with the Nkx2-5 composite enhancer, as revealed by chromatin immunoprecipitation analysis of differentiated P19 cells. Finally, transgenic mice containing the Smad/GATA composite enhancer recapitulated early murine Nkx2-5 cardiac expression and deletion of this enhancer within a 10-kb transgene pBS-Nkx2-5 LacZ significantly reduced expression in the cardiac crescent. Thus, integration of GATA transcription factors with BMP signaling, through co-association with Smads factors, may initiate early Nkx2-5 expression; suggesting a vital role for the combination of these factors in the specification of cardiac progenitors.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Bone Morphogenetic Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Chromatin,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/GATA4 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/Glutathione Transferase,
http://linkedlifedata.com/resource/pubmed/chemical/Homeodomain Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/NKX2-5 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Smad Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Smad1 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Smad1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Smad4 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Smad4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
12
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pubmed:volume |
279
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
10659-69
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:14662776-Animals,
pubmed-meshheading:14662776-Base Sequence,
pubmed-meshheading:14662776-Binding Sites,
pubmed-meshheading:14662776-Bone Morphogenetic Proteins,
pubmed-meshheading:14662776-Cell Differentiation,
pubmed-meshheading:14662776-Cell Line,
pubmed-meshheading:14662776-Cell Lineage,
pubmed-meshheading:14662776-Chromatin,
pubmed-meshheading:14662776-DNA-Binding Proteins,
pubmed-meshheading:14662776-Enhancer Elements, Genetic,
pubmed-meshheading:14662776-GATA4 Transcription Factor,
pubmed-meshheading:14662776-Gene Deletion,
pubmed-meshheading:14662776-Genes, Reporter,
pubmed-meshheading:14662776-Genetic Vectors,
pubmed-meshheading:14662776-Glutathione Transferase,
pubmed-meshheading:14662776-Homeodomain Proteins,
pubmed-meshheading:14662776-Luciferases,
pubmed-meshheading:14662776-Mice,
pubmed-meshheading:14662776-Mice, Transgenic,
pubmed-meshheading:14662776-Models, Genetic,
pubmed-meshheading:14662776-Molecular Sequence Data,
pubmed-meshheading:14662776-Mutation,
pubmed-meshheading:14662776-Precipitin Tests,
pubmed-meshheading:14662776-Promoter Regions, Genetic,
pubmed-meshheading:14662776-Protein Binding,
pubmed-meshheading:14662776-Protein Structure, Tertiary,
pubmed-meshheading:14662776-Signal Transduction,
pubmed-meshheading:14662776-Smad Proteins,
pubmed-meshheading:14662776-Smad1 Protein,
pubmed-meshheading:14662776-Smad4 Protein,
pubmed-meshheading:14662776-Trans-Activators,
pubmed-meshheading:14662776-Transcription, Genetic,
pubmed-meshheading:14662776-Transcription Factors,
pubmed-meshheading:14662776-Two-Hybrid System Techniques,
pubmed-meshheading:14662776-Zinc Fingers
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pubmed:year |
2004
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pubmed:articleTitle |
The cardiac determination factor, Nkx2-5, is activated by mutual cofactors GATA-4 and Smad1/4 via a novel upstream enhancer.
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pubmed:affiliation |
Department of Molecular and Cellular Biology, The Center for Cardiovascular Development, Baylor College of Medicine, Houston, Texas 77030, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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