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PMID:19674970

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Citation

Song, H, Suehiro, J, Kanki, Y, Kawai, Y, Inoue, K, Daida, H, Yano, K, Ohhashi, T, Oettgen, P, Aird, WC, Kodama, T and Minami, T (2009) Critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells. J. Biol. Chem. 284:29109-24

Abstract

Endothelial phenotypes are highly regulated in space and time by both transcriptional and post-transcriptional mechanisms. There is increasing evidence that the GATA family of transcription factors function as signal transducers, coupling changes in the extracellular environment to changes in downstream target gene expression. Here we show that human primary endothelial cells derived from large blood vessels express GATA2, -3, and -6. Of these factors, GATA3 was expressed at the highest levels. In DNA microarrays of human umbilical vein endothelial cells (HUVEC), small interfering RNA-mediated knockdown of GATA3 resulted in reduced expression of genes associated with angiogenesis, including Tie2. At a functional level, GATA3 knockdown inhibited angiopoietin (Ang)-1-mediated but not vascular endothelial cell growth factor (VEGF)-mediated AKT signaling, cell migration, survival, and tube formation. In electrophoretic gel mobility shift assays and chromatin immunoprecipitation, GATA3 was shown to bind to regulatory regions within the 5'-untranslated region of the Tie2 gene. In co-immunoprecipitation and co-transfection assays, GATA3 and the Ets transcription factor, ELF1, physically interacted and synergized to transactivate the Tie2 promoter. GATA3 knockdown blocked the ability of Ang-1 to attenuate vascular endothelial cell growth factor stimulation of vascular cell adhesion molecule-1 expression and monocytic cell adhesion. Moreover, exposure of human umbilical vein endothelial cells to tumor necrosis factor-alpha resulted in marked down-regulation of GATA3 expression and reduction in Tie2 expression. Together, these findings suggest that GATA3 is indispensable for Ang-1-Tie2-mediated signaling in large vessel endothelial cells.

Links

PubMed PMC2781456 Online version:10.1074/jbc.M109.041145

Keywords

Angiopoietin-1/metabolism; Endothelial Cells/cytology; Endothelium, Vascular/cytology; Endothelium, Vascular/metabolism; GATA3 Transcription Factor/metabolism; GATA3 Transcription Factor/physiology; Gene Expression Regulation; Humans; Immunoprecipitation; Oligonucleotide Array Sequence Analysis; Phenotype; Promoter Regions, Genetic; RNA, Small Interfering/metabolism; Receptor, TIE-2/biosynthesis; Receptor, TIE-2/chemistry; Tumor Necrosis Factor-alpha/metabolism; Umbilical Veins/cytology; Vascular Endothelial Growth Factor A/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:GATA3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15723

F

Seeded From UniProt

complete

HUMAN:GATA3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P32519

F

Seeded From UniProt

complete

HUMAN:GATA3

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GATA3

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GATA3

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000315: mutant phenotype evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

HUMAN:ELF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P23771

F

Seeded From UniProt

complete

HUMAN:ELF1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ANGP1

involved_in

GO:0007162: negative regulation of cell adhesion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ANGP1

involved_in

GO:2000352: negative regulation of endothelial cell apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ELF2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P23771

F

Seeded From UniProt

complete

HUMAN:GATA3

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA3

involved_in

GO:2000352: negative regulation of endothelial cell apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA3

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA3

involved_in

GO:0071356: cellular response to tumor necrosis factor

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA3

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA3

involved_in

GO:0050728: negative regulation of inflammatory response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA3

involved_in

GO:0010595: positive regulation of endothelial cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA3

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GATA3

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GATA3

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000315: mutant phenotype evidence used in manual assertion

F

occurs_at:(SO:0001952)

Seeded From UniProt

complete

HUMAN:GATA3

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GATA3

involved_in

GO:0009967: positive regulation of signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0045785: positive regulation of cell adhesion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ELF1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ELF1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ELF1

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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