Cited by 588Angiogenesis and VEGF in CancerCancer, Hypoxia, and MetabolismRedox biology and oxidative stress

JunD Reduces Tumor Angiogenesis by Protecting Cells from Oxidative Stress

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Gerald, Damien, Berra, Edurne, Frapart, Yves M., Chan, Denise A., Giaccia, Amato J., Mansuy, Daniel, Pouysségur, Jacques, Yaniv, Moshe +1 more·2004·Cell

Abstract

Reactive oxygen species (ROS) are implicated in the pathophysiology of various diseases, including cancer. In this study, we show that JunD, a member of the AP-1 family of transcription factors, reduces tumor angiogenesis by limiting Ras-mediated production of ROS. Using junD-deficient cells, we demonstrate that JunD regulates genes involved in antioxidant defense, H2O2 production, and angiogenesis. The accumulation of H2O2 in junD-/- cells decreases the availability of FeII and reduces the activity of HIF prolyl hydroxylases (PHDs) that target hypoxia-inducible factors-alpha (HIFalpha) for degradation. Subsequently, HIF-alpha proteins accumulate and enhance the transcription of VEGF-A, a potent proangiogenic factor. Our study uncovers the mechanism by which JunD protects cells from oxidative stress and exerts an antiangiogenic effect. Furthermore, we provide new insights into the regulation of PHD activity, allowing immediate reactive adaptation to changes in O2 or iron levels in the cell.

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Crossref · 10.1016/j.cell.2004.08.025

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  • Tf bound with iron releases iron at acidic pH because of major conformational changes including a 54- to 63-degree rotation between the two domains on each lobe.

    “Tf bound with iron releases iron at acidic pH because of major conformational changes including a 54- to 63-degree rotation between the two domains on each lobe (103).”

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Authors
Gerald, D., Berra, E., Frapart, Y. M., Chan, D. A., Giaccia, A. J., Mansuy, D., Pouysségur, J., Yaniv, M., & Mechta-Grigoriou, F.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Stanford Medicine (US)
Venue
Cell
Publisher
Elsevier BV
Published
2004-09
Volume
118
Issue
6
Pages
781-794
ISSN
0092-8674 (ISSN-L)
OpenAlex
W1963545628
Cited by
588
References
60
Citations by year
2026: 13 · 2025: 16 · 2024: 19 · 2023: 18 · 2022: 14 · 2021: 27 · 2020: 10 · 2019: 20 · 2018: 15 · 2017: 15 · 2016: 25 · 2015: 25 · 2014: 36 · 2013: 33 · 2012: 32
FWCI
13.50
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
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 › Redox biology and oxidative stress
Keywords
JunD, tumor angiogenesis, oxidative stress, reactive oxygen species, AP-1 transcription factor, Ras signaling, hydrogen peroxide, HIF prolyl hydroxylase, hypoxia, VEGF-A, antioxidant defense, iron availability, antiangiogenic activity
MeSH terms
Animals, Antioxidants, Humans, Hydrogen Peroxide, Iron, Neoplasms, Neovascularization, Pathologic, Procollagen-Proline Dioxygenase, Transcription Factors, Up-Regulation, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-jun, Reactive Oxygen Species, Oxidative Stress, ras Proteins, Vascular Endothelial Growth Factor A, Dioxygenases, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases

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