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PMID:18059339

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Citation

Liu, D, Evans, I, Britton, G and Zachary, I (2008) The zinc-finger transcription factor, early growth response 3, mediates VEGF-induced angiogenesis. Oncogene 27:2989-98

Abstract

Early growth response 3 (Egr3) is a member of a zinc-finger transcription factor subfamily, which we previously found to be strongly upregulated by vascular endothelial growth factor (VEGF)-A in an oligonucleotide microarray screen of endothelial cells. Here, we show that Egr3 is the predominant Egr family member upregulated by VEGF in endothelial cells at 45 min, and that VEGF induced a rapid increase in Egr-dependent transcriptional activation mediated via its major signalling receptor, VEGFR2/KDR, and the protein kinase C (PKC) pathway. VEGF-induced Egr3 gene expression was also mediated in part via a PKC-dependent activation of protein kinase D. Inhibition of Egr3 gene expression by RNA interference was effective in inhibiting basal and VEGF-induced Egr3 gene expression, and it also inhibited VEGF-mediated endothelial cell proliferation, migration and tubulogenesis. These findings indicate that Egr3 has an essential downstream role in VEGF-mediated endothelial functions leading to angiogenesis and may have particular relevance for adult angiogenic processes involved in vascular repair and neovascular disease.

Links

PubMed Online version:10.1038/sj.onc.1210959

Keywords

Base Sequence; Cell Proliferation; Cells, Cultured; DNA Primers; Early Growth Response Protein 3/genetics; Early Growth Response Protein 3/physiology; Endothelium, Vascular/cytology; Gene Expression Regulation/physiology; Humans; Neovascularization, Physiologic; Oligonucleotide Array Sequence Analysis; Protein Kinase C/metabolism; RNA, Small Interfering; Reverse Transcriptase Polymerase Chain Reaction; Transcriptional Activation; Up-Regulation; Vascular Endothelial Growth Factor A/physiology

Significance

Annotations

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

HUMAN:FGF2

enables

GO:0008083: growth factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:FGF2

involved_in

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:FGF2

involved_in

GO:0001938: positive regulation of endothelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:FGF2

enables

GO:0005125: cytokine activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:FGF2

enables

GO:0042056: chemoattractant activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:FGF2

involved_in

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

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0032147: activation of protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:VEGFA

enables

GO:0042056: chemoattractant activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

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

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0090037: positive regulation of protein kinase C signaling

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:NR4A1

involved_in

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:NR4A1

involved_in

GO:0001938: positive regulation of endothelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:NR4A1

involved_in

GO:0044344: cellular response to fibroblast growth factor stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:NR4A1

involved_in

GO:0035924: cellular response to vascular endothelial growth factor stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:NR4A1

involved_in

GO:0035767: endothelial cell chemotaxis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:EGR3

involved_in

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:EGR3

involved_in

GO:0001938: positive regulation of endothelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:EGR3

involved_in

GO:0044344: cellular response to fibroblast growth factor stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:EGR3

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:EGR3

involved_in

GO:0035924: cellular response to vascular endothelial growth factor stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:EGR3

involved_in

GO:0035767: endothelial cell chemotaxis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

GO:0048010: vascular endothelial growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

GO:0035924: cellular response to vascular endothelial growth factor stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

GO:0035556: intracellular signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

GO:0048010: vascular endothelial growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

GO:0035924: cellular response to vascular endothelial growth factor stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

GO:0035556: intracellular signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

GO:0048010: vascular endothelial growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

GO:0035924: cellular response to vascular endothelial growth factor stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

GO:0035556: intracellular signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0090037: positive regulation of protein kinase C signaling

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

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

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0002042: cell migration involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0032147: activation of protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:VEGFA

enables

GO:0042056: chemoattractant activity

ECO:0000314: direct assay evidence used in manual assertion

F

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

GO:0035556: intracellular signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

GO:0035924: cellular response to vascular endothelial growth factor stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

GO:0048010: vascular endothelial growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0002618)

Seeded From UniProt

complete


See also

References

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