Hypoxia and Reactive Oxygen Species
In recent years, superoxide and other reactive oxygen species (ROS) have been acknowledged to act not only as unwanted and even toxic byproducts of aerobic metabolism but also as important signaling molecules in various physiological and pathophysiological conditions. This has broadened the field of oxygen signaling in a substantial way given the fact that superoxide is derived from molecular oxygen. In this regard ROS and ROS-dependent signaling pathways appear to be connected in different ways to the pathways involved in the adaptation towards a low-oxygen environment.
One of the major pathways regulated by oxygen availability relies on the activity of hypoxia-inducible transcription factors (HIFs). Originally described to be only induced and activated under hypoxia, accumulating evidence suggests that HIFs play a more general role in response to diverse cellular activators and stressors, many of which use ROS as signal transducers. On the other hand, the HIF pathway has also been implicated in controlling some important ROS-generating systems. Thus, an important cross talk exists between ROS signaling systems and the HIF pathway which may have substantial consequences for the pathogenesis of various disorders including cancer.
KeywordsNADPH oxidase HIF Hypoxia Reactive oxygen species NFkB Tumor Signaling
This work was supported by DFG GO709/4-5 and the Seventh European Framework Programme (Metoxia).
- Belaiba RS, Bonello S, Zahringer C, Schmidt S, Hess J et al (2007a) Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells. Mol Biol Cell 18:4691–4697Google Scholar
- BelAiba RS, Djordjevic T, Petry A, Diemer K, Bonello S et al (2007b) NOX5 variants are functionally active in endothelial cells. Free Radic Biol Med 42:446–459Google Scholar
- Diebold I, Flugel D, Becht S, Belaiba RS, Bonello S et al (2010a) The hypoxia-inducible factor-2alpha is stabilized by oxidative stress involving NOX4. Antioxid Redox Signal 13:425–436Google Scholar
- Diebold I, Petry A, Djordjevic T, Belaiba RS, Fineman J et al (2010b) Reciprocal regulation of Rac1 and PAK-1 by HIF-1alpha: a positive-feedback loop promoting pulmonary vascular remodeling. Antioxid Redox Signal 13:399–412Google Scholar
- Diebold I, Petry A, Hess J, Gorlach A (2010c) The NADPH oxidase subunit NOX4 is a new target gene of the hypoxia-inducible factor-1. Mol Biol Cell 21:2087–2096Google Scholar
- Djordjevic T, BelAiba RS, Bonello S, Pfeilschifter J, Hess J et al (2005a) Human urotensin II is a novel activator of NADPH oxidase in human pulmonary artery smooth muscle cells. Arterioscler Thromb Vasc Biol 25:519–525Google Scholar
- Djordjevic T, Pogrebniak A, BelAiba RS, Bonello S, Wotzlaw C et al (2005b) The expression of the NADPH oxidase subunit p22phox is regulated by a redox-sensitive pathway in endothelial cells. Free Radic Biol Med 38:616–630Google Scholar
- Gorlach A, Brandes RP, Nguyen K, Amidi M, Dehghani F et al (2000a) A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall. Circ Res 87:26–32Google Scholar
- Görlach A, Camenisch G, Kvietikova I, Vogt L, Wenger RH et al (2000b) Efficient translation of mouse hypoxia-inducible factor-1alpha under normoxic and hypoxic conditions. Biochim Biophys Acta 1493:125–134Google Scholar
- Kleikers PW, Wingler K, Hermans JJ, Diebold I, Altenhofer S et al (2012) NADPH oxidases as a source of oxidative stress and molecular target in ischemia/reperfusion injury. J Mol Med (Berl) 90:1391–1406Google Scholar
- Koshikawa N, Hayashi J, Nakagawara A, Takenaga K (2009) Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1alpha gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway. J Biol Chem 284:33185–33194PubMedGoogle Scholar
- Liu JQ, Zelko IN, Erbynn EM, Sham JS, Folz RJ (2006a) Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol 290:L2–L10Google Scholar
- Liu LZ, Hu XW, Xia C, He J, Zhou Q et al (2006b) Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radic Biol Med 41:1521–1533Google Scholar
- Schulz E, Wenzel P, Munzel T, Daiber A (2012) Mitochondrial redox signaling: interaction of mitochondrial reactive oxygen species with other sources of oxidative stress. Antioxid Redox SignalGoogle Scholar
- Tuttle SW, Maity A, Oprysko PR, Kachur AV, Ayene IS et al (2007) Detection of reactive oxygen species via endogenous oxidative pentose phosphate cycle activity in response to oxygen concentration: implications for the mechanism of HIF-1alpha stabilization under moderate hypoxia. J Biol Chem 282:36790–36796PubMedGoogle Scholar
- Wang GL, Jiang BH,SemenzaGL(1995) Effect of altered redox states on expression and DNA-binding activity of hypoxia-inducible factor 1. Biochem Biophys Res Commun 212(2):550–556Google Scholar
- Welsh SJ, Bellamy WT, Briehl MM, Powis G (2002) The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 62:5089–5095PubMedGoogle Scholar
- Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C et al (2000) Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60:1541–1545PubMedGoogle Scholar
- Zhou J, Callapina M, Goodall GJ, Brune B (2004) Functional integrity of nuclear factor kappaB, phosphatidylinositol 3’-kinase, and mitogen-activated protein kinase signaling allows tumor necrosis factor alpha-evoked Bcl-2 expression to provoke internal ribosome entry site-dependent translation of hypoxia-inducible factor 1alpha. Cancer Res 64:9041–9048PubMedGoogle Scholar