Post-transcriptional Regulation of Vascular Endothelial Growth Factor by Hypoxia
Open accessAbstract
The major control point for the hypoxic induction of the vascular endothelial growth factor (VEGF) gene is the regulation of the steady-state level of the mRNA. We previously demonstrated a discrepancy between the transcription rate and the steady-state mRNA level induced by hypoxia. This led us to examine the post-transcriptional regulation of VEGF expression. Actinomycin D experiments revealed that hypoxia increased VEGF mRNA half-life from 43 +/- 6 min to 106 +/- 9 min. Using an in vitro mRNA degradation assay, the half-life of VEGF mRNA 3'-untranslated region (UTR) transcripts were also found to be increased when incubated with hypoxic versus normoxic extracts. Both cis-regulatory elements involved in VEGF mRNA degradation under normoxic conditions and in increased stabilization under hypoxic conditions were mapped using this degradation assay. A hypoxia-induced protein(s) was found that bound to the sequences in the VEGF 3'-UTR which mediated increased stability in the degradation assay. Furthermore, genistein, a tyrosine kinase inhibitor, blocked the hypoxia-induced stabilization of VEGF 3'-UTR transcripts and inhibited hypoxia-induced protein binding to the VEGF 3'-UTR. These findings demonstrate a significant post-transcriptional component to the regulation of VEGF.
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The half-life of the mRNA encoding VEGF is more than doubled under hypoxic conditions, favoring angiogenesis.
“By contrast, the half-life of the mRNA encoding VEGF is more than doubled under hypoxic conditions (334), again favoring angiogenesis.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [334]
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- Authors
- Levy, A. P., Levy, N. S., & Goldberg, M. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Goldberg, Mark A.
- ORCID
- Levy, Andrew P.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1996-02
- Volume
- 271
- Issue
- 5
- Pages
- 2746-2753
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2038750685
- Cited by
- 629
- References
- 32
- Citations by year
- 2024: 4 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 6 · 2019: 6 · 2018: 5 · 2017: 9 · 2016: 8 · 2015: 16 · 2014: 14 · 2013: 15 · 2012: 11
- FWCI
- 17.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (T32HL07604, 1KO8HL03405-01, 1F32HL08838-02, DK45098)
- American Heart Association Grant-in-Aid
- American Heart Association Established Investigator Award
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- 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
- Keywords
- vascular endothelial growth factor, hypoxia, post-transcriptional regulation, mRNA stability, mRNA half-life, 3' untranslated region, cis-regulatory elements, mRNA degradation, genistein, tyrosine kinase inhibition
- MeSH terms
- Animals, Base Sequence, Cell-Free System, Isoflavones, Lymphokines, Molecular Sequence Data, RNA Processing, Post-Transcriptional, RNA, Messenger, Transcription, Genetic, Cell Hypoxia, Endothelial Growth Factors, PC12 Cells, Genistein, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Rats
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