JunD reduces tumor angiogenesis by protecting cells from oxidative stress.
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.
Gerald
Damien
D
Unit of Gene Expression and Diseases, CNRS URA 1644, Pasteur Institute, 25 Rue du Docteur Roux, 75724 Paris, Cedex 15, France.
Berra
Edurne
E
Frapart
Yves M
YM
Chan
Denise A
DA
Giaccia
Amato J
AJ
Mansuy
Daniel
D
Pouysségur
Jacques
J
Yaniv
Moshe
M
Mechta-Grigoriou
Fatima
F
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D049308:Dioxygenases; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007501:Iron / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018384:Oxidative Stress / Q000235:genetics; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D000975:Antioxidants; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D006861:Hydrogen Peroxide; D007501:Iron; D049308:Dioxygenases; D011393:Procollagen-Proline Dioxygenase; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D018631:ras Proteins