JunD reduces tumor angiogenesis by protecting cells from oxidative stress

Damien Gerald; Edurne Berra; Yves M Frapart; Denise A Chan; Amato J Giaccia; Daniel Mansuy; Jacques Pouysségur; Moshe Yaniv; Fatima Mechta-Grigoriou

doi:10.1016/j.cell.2004.08.025

JunD reduces tumor angiogenesis by protecting cells from oxidative stress

Cell. 2004 Sep 17;118(6):781-94. doi: 10.1016/j.cell.2004.08.025.

Authors

Damien Gerald¹, Edurne Berra, Yves M Frapart, Denise A Chan, Amato J Giaccia, Daniel Mansuy, Jacques Pouysségur, Moshe Yaniv, Fatima Mechta-Grigoriou

Affiliation

¹ Unit of Gene Expression and Diseases, CNRS URA 1644, Pasteur Institute, 25 Rue du Docteur Roux, 75724 Paris, Cedex 15, France.

PMID: 15369676
DOI: 10.1016/j.cell.2004.08.025

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antioxidants / metabolism
Dioxygenases
Gene Expression Regulation, Neoplastic / genetics
Humans
Hydrogen Peroxide / metabolism
Hypoxia-Inducible Factor 1, alpha Subunit
Hypoxia-Inducible Factor-Proline Dioxygenases
Iron / metabolism
Neoplasms / blood supply*
Neoplasms / genetics
Neoplasms / metabolism*
Neovascularization, Pathologic / genetics
Neovascularization, Pathologic / metabolism*
Neovascularization, Pathologic / physiopathology
Oxidative Stress* / genetics
Procollagen-Proline Dioxygenase / metabolism
Proto-Oncogene Proteins c-jun / genetics
Proto-Oncogene Proteins c-jun / physiology*
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / metabolism*
Transcription Factors / metabolism
Up-Regulation / genetics
Vascular Endothelial Growth Factor A / metabolism
ras Proteins / metabolism

Substances

Antioxidants
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Proto-Oncogene Proteins c-jun
Reactive Oxygen Species
Transcription Factors
Vascular Endothelial Growth Factor A
Hydrogen Peroxide
Iron
Dioxygenases
Procollagen-Proline Dioxygenase
EGLN3 protein, human
Hypoxia-Inducible Factor-Proline Dioxygenases
ras Proteins