Differential Transcriptional Regulation of the Two Vascular Endothelial Growth Factor Receptor Genes

Gerber, Hans-Peter; Condorelli, Fabrizio; Park, Jeanie; Ferrara, Napoleone

doi:10.1074/jbc.272.38.23659

Cited by 794Angiogenesis and VEGF in CancerCancer, Hypoxia, and MetabolismKruppel-like factors research

Differential Transcriptional Regulation of the Two Vascular Endothelial Growth Factor Receptor Genes

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Gerber, Hans-Peter, Condorelli, Fabrizio, Park, Jeanie, Ferrara, Napoleone·1997·Journal of Biological Chemistry

DOI 10.1074/jbc.272.38.23659

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Abstract

Vascular endothelial growth factor (VEGF) and its two endothelial cell-specific receptor tyrosine kinases, Flk-1/KDR and Flt-1, play a key role in physiological and pathological angiogenesis. Hypoxia has been shown to be a major mechanism for up-regulation of VEGF and its receptors in vivo. When we exposed human umbilical vein endothelial cells to hypoxic conditions in vitro, we observed increased levels of Flt-1 expression. In contrast, Flk-1/KDR mRNA levels were unchanged or slightly repressed. These findings suggest a differential transcriptional regulation of the two receptors by hypoxia. To identify regulatory elements involved in the hypoxic response, promoter regions of the mouse Flt-1 and Flk-1/KDR genes were isolated and tested in conjunction with luciferase reporter gene. In transient transfection assays, hypoxia led to strong transcriptional activation of the Flt-1 promoter, whereas Flk-1/KDR transcription was essentially unchanged. Promoter deletion analysis demonstrated a 430-bp region of the Flt-1 promoter to be required for transcriptional activation in response to hypoxia. This region includes a heptamer sequence matching the hypoxia-inducible factor-1 (HIF) consensus binding site previously found in other hypoxia-inducible genes such as the VEGF gene and erythropoietin gene. We further narrowed down the element mediating the hypoxia response to a 40-base pair sequence including the putative HIF binding site. We show that this element acts like an enhancer, since it activated transcription irrespective of its location or orientation in the construct. Furthermore, mutations within the putative HIF consensus binding site lead to impaired transcriptional activation by hypoxia. These findings indicate that, unlike the KDR/Flk-1 gene, the Flt-1 receptor gene is directly up-regulated by hypoxia via a hypoxia-inducible enhancer element located at positions -976 to -937 of the Flt-1 promoter.

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Macrophage-secreted growth factors such as VEGF, VEGFR1, VEGFR2, PDGF, FGF, and TGF-β are induced by hypoxia.
“Macrophage-secreted growth factors such as vascular endothelial growth factor (VEGF) and its receptor VEGFR1 and VEGFR2, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factor-β (TGF-β) have been reported to be induced by hypoxia [76,77,78].”
From The Pathogenesis of Adenomyosis vis-à-vis Endometriosis (2020) · cites this paper as [77]

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Authors: Gerber, H.-P., Condorelli, F., Park, J., & Ferrara, N.
Affiliations: Genentech (US)
Corresponding author: Ferrara, Napoleone
ORCID: Gerber, Hans-Peter
Condorelli, Fabrizio
Park, Jeanie
Ferrara, Napoleone
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1997-09
Volume: 272
Issue: 38
Pages: 23659-23667
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.272.38.23659
OpenAlex: W2020968632
Cited by: 794
References: 50
Citations by year: 2026: 5 · 2025: 9 · 2024: 10 · 2023: 10 · 2022: 18 · 2021: 19 · 2020: 14 · 2019: 13 · 2018: 21 · 2017: 14 · 2016: 7 · 2015: 30 · 2014: 24 · 2013: 32 · 2012: 34
FWCI: 9.36
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 8435 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
Keywords: vascular endothelial growth factor receptor, Flt-1, KDR/Flk-1, hypoxia, transcriptional regulation, HIF-1, enhancers, promoter analysis, angiogenesis, human umbilical vein endothelial cells, VEGF receptors
MeSH terms: Amino Acid Sequence, Animals, Base Sequence, Cell Line, HeLa Cells, Humans, Molecular Sequence Data, Proto-Oncogene Proteins, RNA, Messenger, Sequence Homology, Nucleic Acid, Transcription, Genetic, Cell Hypoxia, Up-Regulation, Endothelial Growth Factors, Receptors, Growth Factor, Receptor Protein-Tyrosine Kinases, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor Receptor-1, Mice

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Differential Transcriptional Regulation of the Two Vascular Endothelial Growth Factor Receptor Genes

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