Regulation of Hypoxia‐Inducible Factor‐1a by Reactive Oxygen Species : New Developments in an Old Debate

Hypoxia‐Inducible Factor‐1 (HIF‐1) has been largely studied for its role in cell survival in hypoxic conditions. The regulation of HIF‐1 is a complex process and involves a number of molecules and pathways. Among these mechanisms a direct regulatory role of reactive oxygen species (ROS) on HIF‐1 alpha subunit has received a great deal of attention and the existing body of literature includes many contradictory findings. Other intermediates such as nitric oxide (NO), specific microRNAs (miR), and transcriptional and post‐translational modification have also been implicated as players in ROS mediated HIF‐1a regulation. The focus of this review is to present the past conflicting evidence along with more recent findings in order to relate various aspects of this complex process. Aside from the direct role of ROS on HIF‐1a regulation under hypoxia and normoxia, we analyzed the effect of different sources and concentrations of NO and the interplay between superoxide (SO) and NO in this process. We also present findings on transcriptional and translational regulation of HIF‐1a via ROS and the interplay with microRNAs in this process. This review further provides insight on ERK and PI3K/AKT signaling as a common mechanism relating several pathways of ROS mediated HIF‐1a regulation. Ultimately further research and discovery regarding HIF‐1 regulation by oxidative stress is warranted for better understanding of disease development and potential therapeutics for pathologies such as cancer, inflammatory diseases, and ischemia‐reperfusion injury. J. Cell. Biochem. 116: 696–703, 2015. © 2014 Wiley Periodicals, Inc.

[1]  S. Gerecht,et al.  Hypoxia and free radicals: role in tumor progression and the use of engineering-based platforms to address these relationships. , 2015, Free radical biology & medicine.

[2]  M. Pallàs,et al.  Evaluation of hypoxia inducible factor expression in inflammatory and neurodegenerative brain models. , 2013, The international journal of biochemistry & cell biology.

[3]  J. Kim,et al.  Reactive oxygen species-responsive miR-210 regulates proliferation and migration of adipose-derived stem cells via PTPN2 , 2013, Cell Death and Disease.

[4]  T. Hagen.  Oxygen versus Reactive Oxygen in the Regulation of HIF-1α: The Balance Tips , 2012, Biochemistry research international.

[5]  A. Petry,et al.  Inhibition of endothelial nitric oxyde synthase increases capillary formation via Rac1-dependent induction of hypoxia-inducible factor-1α and plasminogen activator inhibitor-1 , 2012, Thrombosis and Haemostasis.

[6]  Huichen Wang,et al.  MicroRNA-21 modulates the levels of reactive oxygen species by targeting SOD3 and TNFα. , 2012, Cancer research.

[7]  Rachelle S. Singleton,et al.  The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity , 2012, EMBO reports.

[8]  F. Domann,et al.  Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2(-•) and H2O2. , 2012, Free radical biology & medicine.

[9]  Huichen Wang,et al.  MicroRNA-21 Modulates the Levels of Reactive Oxygen Species Levels by Targeting SOD 3 and TNF α , 2012 .

[10]  R. Mutharasan,et al.  microRNA-210 is upregulated in hypoxic cardiomyocytes through Akt- and p53-dependent pathways and exerts cytoprotective effects. , 2011, American journal of physiology. Heart and circulatory physiology.

[11]  Jun Du,et al.  PI3K and ERK-Induced Rac1 Activation Mediates Hypoxia-Induced HIF-1α Expression in MCF-7 Breast Cancer Cells , 2011, PloS one.

[12]  Jing Yang,et al.  Phosphatidylinositol 3'-kinase signaling pathway is essential for Rac1-induced hypoxia-inducible factor-1(alpha) and vascular endothelial growth factor expression. , 2011, American journal of physiology. Heart and circulatory physiology.

[13]  B. Jiang,et al.  MiR-21 Induced Angiogenesis through AKT and ERK Activation and HIF-1α Expression , 2011, PloS one.

[14]  P Barbry,et al.  miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity , 2011, Cell Death and Differentiation.

[15]  J. Loscalzo.  The cellular response to hypoxia: tuning the system with microRNAs. , 2010, The Journal of clinical investigation.

[16]  Howard T. Jacobs,et al.  Production of Mitochondrial Reactive Oxygen Species Protein in Hypoxia Occurs Independently α Stabilization of Hypoxia-inducible Factor-1 Cell Biology : , 2010 .

[17]  Tetsuya Yamamoto,et al.  Reactive oxygen species produced by the knockdown of manganese-superoxide dismutase up-regulate hypoxia-inducible factor-1alpha expression in oral squamous cell carcinoma cells. , 2010, Free radical biology & medicine.

[18]  J. Hayashi,et al.  Reactive Oxygen Species-generating Mitochondrial DNA Mutation Up-regulates Hypoxia-inducible Factor-1α Gene Transcription via Phosphatidylinositol 3-Kinase-Akt/Protein Kinase C/Histone Deacetylase Pathway* , 2009, The Journal of Biological Chemistry.

[19]  Ricky T. Tong,et al.  Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. , 2009, Molecular cell.

[20]  Chunxiang Zhang,et al.  Involvement of MicroRNAs in Hydrogen Peroxide-mediated Gene Regulation and Cellular Injury Response in Vascular Smooth Muscle Cells* , 2009, Journal of Biological Chemistry.

[21]  L. Oberley,et al.  Manganese superoxide dismutase modulates hypoxia-inducible factor-1 alpha induction via superoxide. , 2008, Cancer research.

[22]  B. Brüne,et al.  Nitric oxide and superoxide: interference with hypoxic signaling. , 2007, Cardiovascular research.

[23]  J. Eisenbart,et al.  Jcb: Article , 2022 .

[24]  C. Kallenberg,et al.  Regulation of Cytokine‐Induced HIF‐1α Expression in Rheumatoid Synovial Fibroblasts , 2007, Annals of the New York Academy of Sciences.

[25]  B. Brüne,et al.  Hypoxia‐Inducible Factor‐1α Under the Control of Nitric Oxide , 2007 .

[26]  James B. Mitchell,et al.  Superoxide Fluxes Limit Nitric Oxide-induced Signaling* , 2006, Journal of Biological Chemistry.

[27]  B. Brüne,et al.  Reactive oxygen species attenuate nitric-oxide-mediated hypoxia-inducible factor-1α stabilization , 2006 .

[28]  P. Schumacker,et al.  Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. , 2005, Cell metabolism.

[29]  Massimo Zeviani,et al.  Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. , 2005, Cell metabolism.

[30]  G. Semenza,et al.  Hydroxylation of HIF-1: oxygen sensing at the molecular level. , 2004, Physiology.

[31]  G. Semenza,et al.  Nitric Oxide Induces Hypoxia-inducible Factor 1 Activation That Is Dependent on MAPK and Phosphatidylinositol 3-Kinase Signaling* , 2004, Journal of Biological Chemistry.

[32]  S. Moncada,et al.  Regulation of hypoxia-inducible factor-1alpha by nitric oxide through mitochondria-dependent and -independent pathways. , 2003, The Biochemical journal.

[33]  I. Yasinska,et al.  S‐nitrosation of Cys‐800 of HIF‐1α protein activates its interaction with p300 and stimulates its transcriptional activity , 2003, FEBS letters.

[34]  B. Brüne,et al.  Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. , 2003, Molecular biology of the cell.

[35]  N. Sang,et al.  MAPK Signaling Up-regulates the Activity of Hypoxia-inducible Factors by Its Effects on p300* , 2003, The Journal of Biological Chemistry.

[36]  B. Brüne,et al.  HIF‐1α protein as a target for S‐nitrosation , 2003, FEBS letters.

[37]  Jong-Wan Park,et al.  Oxygen-dependent and -independent regulation of HIF-1alpha. , 2002, Journal of Korean medical science.

[38]  J. Haddad.  Redox regulation of pro-inflammatory cytokines and Iκb-α/NF-κB nuclear translocation and activation , 2002 .

[39]  J. Haddad.  The involvement of L-gamma-glutamyl-L-cysteinyl-glycine (glutathione/GSH) in the mechanism of redox signaling mediating MAPK(p38)-dependent regulation of pro-inflammatory cytokine production. , 2002, Biochemical pharmacology.

[40]  G. Lenaz.  The Mitochondrial Production of Reactive Oxygen Species: Mechanisms and Implications in Human Pathology , 2001, IUBMB life.

[41]  M. Ivan,et al.  HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing , 2001, Science.

[42]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[43]  B. Brüne,et al.  Accumulation of HIF-1alpha under the influence of nitric oxide. , 2001, Blood.

[44]  R. Johns,et al.  Normoxic stabilization of hypoxia-inducible factor-1 expression and activity: redox-dependent effect of nitrogen oxides. , 2000, Molecular pharmacology.

[45]  B. Brüne,et al.  Induction of hypoxia-inducible-factor 1 by nitric oxide is mediated via the PI 3K pathway. , 2000, Biochemical and biophysical research communications.

[46]  N. Chandel,et al.  Reactive Oxygen Species Generated at Mitochondrial Complex III Stabilize Hypoxia-inducible Factor-1α during Hypoxia , 2000, The Journal of Biological Chemistry.

[47]  J. Haddad,et al.  Antioxidant/Pro-oxidant Equilibrium Regulates HIF-1α and NF-κB Redox Sensitivity , 2000, The Journal of Biological Chemistry.

[48]  J. Haddad,et al.  Antioxidant/pro-oxidant equilibrium regulates HIF-1alpha and NF-kappa B redox sensitivity. Evidence for inhibition by glutathione oxidation in alveolar epithelial cells. , 2000, The Journal of biological chemistry.

[49]  M. Makuuchi,et al.  Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. , 2000, Blood.

[50]  M. Goldberg,et al.  Inhibition of Hypoxia-inducible Factor 1 Activation by Carbon Monoxide and Nitric Oxide , 1999, The Journal of Biological Chemistry.

[51]  N. Chandel,et al.  Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[52]  P. Ratcliffe,et al.  Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. , 1998, The Journal of experimental biology.

[53]  G. Semenza,et al.  Effect of altered redox states on expression and DNA-binding activity of hypoxia-inducible factor 1. , 1995, Biochemical and biophysical research communications.