Hypoxia in the intestine or solid tumors: A beneficial or deleterious alarm signal?

Abstract

IntroductionThe availability of oxygen in the atmosphere provided protozoans with the ability to meet higher energy demands required for the development of complex multicellular organisms. Consequently, oxygen-dependent cells developed mechanisms to sense and adapt to changes in oxygen levels [1]. In mammals the respiratory, circulatory and nervous system work together to ensure that oxygen levels are precisely maintained, because excess or deficiency of oxygen can lead to cell death and tissue damage [2].The level of oxygen in mammalian tissues is much lower than that in the atmosphere (oxygen partial tension (PO 2 ) = 21.2 kPa). Tissue oxygen can range between 13 kPa in the pulmonary vein down to 2.7 kPa at the interstitial spaces. Intracellular oxygen ranges from 1.3 to 2.7 kPa [3]. In this context, hypoxia is defined as a deficiency in tissue or blood oxygen as compared to physiological levels. HIF-1α has been shown to be stabilized at a PO 2 lower than 2kPa [4].One molecule that plays an important role in mediating adaptive functions to oxygen levels is the hypoxia inducible transcription factor (HIF)-1. HIF-1 is a transcription factor composed of Correspondence: Prof. Muriel Moser e-mail: mmoser@ulb.ac.be two subunits, HIF-1α and HIF-1β (or aryl hydrocarbon receptor nuclear translocator). The beta subunit of HIF is constitutively expressed in mammalian cells, whereas, in the presence of oxygen, the alpha subunit is hydroxylated by proline hydroxylases (PHDs), ubiquitinylated by the von Hippel-Lindau (VHL) protein (E3 ubiquitin ligase), and degraded by the proteasome pathway. Hypoxia leads to stabilization of HIF-1α (through the inhibition of oxygen-dependent PHDs), inducing the transcription of multiple genes unique for each cell type, among them erythropoietin, vascular endothelial growth factor, glycolytic enzymes, etc. (for review see [2]). The transcription function of HIF-1 is also negatively regulated in the presence of oxygen by the dioxygenase factor inhibiting HIF that hydroxylates HIF-1α, thereby preventing the recruitment of the transcriptional machinery [5]. Besides the ubiquitously expressed HIF-1, two paralogs exist in mammals that are also regulated by oxygen: HIF-2 is also widely expressed and plays important roles in erythropoiesis, vascularization, pulmonary development and, more specifically, in iron absorption [6,7]; HIF-3 has been shown to negatively regulates HIF-1 and HIF-2 by competing for the binding on HREs of target genes [8]. A recent report, however, clearly demonstrates that zebrafish Hif-3α has strong transactivation activity and that human HIF-3α isoforms upregulate similar target genes in human cells [9]. Finally, it should be noted that, in addition to hypoxia, other mechanisms [12,13]. Although HIFs appear as major sensors of hypoxia, other transcriptional cascades are triggered at low oxygen tension. In particular, the NF-κB pathway was shown to induce Hif-1α and to be activated by hypoxia through p65 and p50 stabilization and nuclear translocation, linking both pathway...

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