A novel class of vascular endothelial growth factor-responsive genes that require forkhead activity for expression

Md Ruhul Abid, Shu Ching Shih, Hasan H. Otu, Katherine C. Spokes, Yoshiaki Okada, David T. Curiel, Takashi Minami, William C. Aird

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Recently, we have shown that transient phosphorylation and inhibition of the pro-apoptotic transcription factor, forkhead, by vascular endothelial growth factor (VEGF) is essential for endothelial cell (EC) survival and proliferation. The goal of the present study was to determine whether forkhead (FKHR) also plays a positive role in agonist-mediated gene induction. Human coronary artery ECs were transduced with adenovirus overexpressing constitutively active phosphorylation-resistant triple mutant FKHR or transfected with small interference RNA (siRNA) against FKHR. The cells were then treated in the absence or presence of VEGF and assayed for gene expression using quantitative real-time PCR and Northern blots analyses. The data revealed a novel set of VEGF-responsive genes that require FKHR activity for optimal expression in ECs, including bone morphogenic protein 2, cbp/p300-interacting transactivator 2, decay accelerating factor (DAF), vascular cell adhesion molecule-1 (VCAM-1), manganese superoxide dismutase, endothelial-specific molecule-1, RING1 and YY1-binding protein, and matrix metalloproteinase-10. Consistent with a positive role for FKHR in mediating VEGF induction of DAF and VCAM-1 mRNA, siRNA against FKHR attenuated the effect of VEGF on complement-mediated EC lysis and monocyte adhesion, respectively. VEGF induction of the forkhead-dependent genes was down-regulated by the NF-κB inhibitor, constitutively active Ad-IκB, and in some cases by the nuclear factor of activated T-cells (NF-AT) inhibitor, cyclosporin. Together, these findings suggest that the VEGF-forkhead signaling axis plays an important functional role in ECs beyond the regulation of cell survival/apoptosis and cell cycle.

Original languageEnglish (US)
Pages (from-to)35544-35553
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number46
DOIs
StatePublished - Nov 17 2006

Fingerprint

Vascular Endothelial Growth Factor A
Genes
CD55 Antigens
Phosphorylation
Vascular Cell Adhesion Molecule-1
Endothelial cells
RNA Interference
Cell Survival
Matrix Metalloproteinase 10
Endothelial Cells
Cells
RNA
NFATC Transcription Factors
Forkhead Transcription Factors
Trans-Activators
Adenoviridae
Gene expression
Northern Blotting
Cyclosporine
Superoxide Dismutase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

A novel class of vascular endothelial growth factor-responsive genes that require forkhead activity for expression. / Abid, Md Ruhul; Shih, Shu Ching; Otu, Hasan H.; Spokes, Katherine C.; Okada, Yoshiaki; Curiel, David T.; Minami, Takashi; Aird, William C.

In: Journal of Biological Chemistry, Vol. 281, No. 46, 17.11.2006, p. 35544-35553.

Research output: Contribution to journalArticle

Abid, Md Ruhul ; Shih, Shu Ching ; Otu, Hasan H. ; Spokes, Katherine C. ; Okada, Yoshiaki ; Curiel, David T. ; Minami, Takashi ; Aird, William C. / A novel class of vascular endothelial growth factor-responsive genes that require forkhead activity for expression. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 46. pp. 35544-35553.
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AB - Recently, we have shown that transient phosphorylation and inhibition of the pro-apoptotic transcription factor, forkhead, by vascular endothelial growth factor (VEGF) is essential for endothelial cell (EC) survival and proliferation. The goal of the present study was to determine whether forkhead (FKHR) also plays a positive role in agonist-mediated gene induction. Human coronary artery ECs were transduced with adenovirus overexpressing constitutively active phosphorylation-resistant triple mutant FKHR or transfected with small interference RNA (siRNA) against FKHR. The cells were then treated in the absence or presence of VEGF and assayed for gene expression using quantitative real-time PCR and Northern blots analyses. The data revealed a novel set of VEGF-responsive genes that require FKHR activity for optimal expression in ECs, including bone morphogenic protein 2, cbp/p300-interacting transactivator 2, decay accelerating factor (DAF), vascular cell adhesion molecule-1 (VCAM-1), manganese superoxide dismutase, endothelial-specific molecule-1, RING1 and YY1-binding protein, and matrix metalloproteinase-10. Consistent with a positive role for FKHR in mediating VEGF induction of DAF and VCAM-1 mRNA, siRNA against FKHR attenuated the effect of VEGF on complement-mediated EC lysis and monocyte adhesion, respectively. VEGF induction of the forkhead-dependent genes was down-regulated by the NF-κB inhibitor, constitutively active Ad-IκB, and in some cases by the nuclear factor of activated T-cells (NF-AT) inhibitor, cyclosporin. Together, these findings suggest that the VEGF-forkhead signaling axis plays an important functional role in ECs beyond the regulation of cell survival/apoptosis and cell cycle.

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