Passing the baton: The HIF switch

Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Trends in Biochemical Sciences (Impact Factor: 13.52). 07/2012; 37(9):364-72. DOI: 10.1016/j.tibs.2012.06.004
Source: PubMed

ABSTRACT Hypoxia is an inadequate oxygen supply to tissues and cells, which can restrict their function. The hypoxic response is primarily mediated by the hypoxia-inducible transcription factors, HIF-1 and HIF-2, which have both overlapping and unique target genes. HIF target gene activation is highly context specific and is not a reliable indicator of which HIF-α isoform is active. For example, in some cell lines, the individual HIFs have specific temporal and functional roles: HIF-1 drives the initial response to hypoxia (<24h) and HIF-2 drives the chronic response (>24h). Here, we review the significance of the HIF switch and the relation between HIF-1 and HIF-2 under both physiological and pathophysiological conditions.

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    • "The HIF family of transcription factors is made up of three oxygen labile subunits, HIF-1α, HIF-2α and HIF-3α, together with a constitutive aryl hydrocarbon receptor nuclear translocator (ARNT or HIF-1β) (Wang et al., 1995). When oxygen is abundant, HIF-1/2α become modified by specific prolyl hydroxylases (PHDs) and ubiquitylated by the von Hippel–Lindau (VHL) E3 ubiquitin ligase promoting HIFα degradation (Koh and Powis, 2005). When oxygen tension is low (hypoxia), the activity of PHD decreases, binding of VHL is lost, degradation of HIF dampens and consequently it accumulates. "
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    ABSTRACT: Within 2 hours of infection by Theileria annulata sporozoites bovine macrophages display a 2-4-fold increase in transcription of HIF-1α. Twenty hours post-invasion sporozoites develop into multi-nucleated macroschizonts that transform the infected macrophage into an immortalized, permanently proliferating, hyper-invasive and disease causing leukemia-like cell. Once immortalized Theileria-infected leukocytes can be propagated as cell lines and even though cultivated under normoxic conditions, both infected B cells and macrophages display sustained activation of HIF-1α. Attenuated macrophages used as live vaccines against tropical theileriosis also display HIF-1α activation even though they have lost their tumorigenic phenotype. Here, we review data that ascribes HIF-1α activation to the proliferation status of the infected leukocyte and discuss the possibility that Theileria may have lost its ability to render its host macrophage virulent due to continuous parasite replication in a high ROS environment. We propose a model, where uninfected macrophages have low levels of H2O2 output, whereas virulent infected macrophages produce high amounts of H2O2. Further increase in H2O2 output leads to dampening of infected macrophage virulence, a characteristic of disease-resistant macrophages. At the same time exposure to H2O2 sustains HIF-1α that induces the switch from mitochondrial oxidative phosphorylation to Warburg glycolysis, a metabolic shift that underpins uncontrolled infected macrophage proliferation. We propose that as macroschizonts develop into merozoites and infected macrophage proliferation arrests, HIF-1α levels will decrease and glycolysis will switch back from Warburg to oxidative glycolysis. As Theileria infection transforms its host leukocyte into an aggressive leukemic-like cell we propose that manipulating ROS levels, HIF-1α induction and oxidative over Warburg glycolysis could contribute to improved disease control. Finally, as excess amounts of H2O2 drive virulent Theileria-infected macrophages towards attenuation it highlights how infection-induced pathology and redox balance are intimately linked.
    Cellular Microbiology 01/2015; 17(4). DOI:10.1111/cmi.12421 · 4.82 Impact Factor
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    • "Among the α-subunits HIF-1α and HIF-2α are best characterized. Both contain an oxygen-dependent degradation domain (ODD) with two conserved prolyl residues [9] [10] that are hydroxylated by prolyl hydroxylases (PHD) 1–3 when sufficient oxygen is available. Once hydroxylated the α-subunits are recognized by the tumor suppressor protein von Hippel– Lindau (pVHL), marked for ubiquitination followed by proteasomal degradation. "
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    ABSTRACT: Hypoxia inducible factors (HIFs) are important mediators of the cellular adaptive response during acute hypoxia. The role of HIF-1 and HIF-2 during prolonged periods of hypoxia, i.e. chronic hypoxia is less defined. Therefore, we used human THP-1 macrophages with a knockdown of either HIF-1α, HIF-2α, or both HIFα-subunits, incubated them for several days under hypoxia (1% O2), and analyzed responses to hypoxia using 2D-DIGE coupled to MS/MS-analysis. Chronic hypoxia was defined as a time point when the early but transient accumulation of HIFα-subunits and mRNA expression of classical HIF target genes returned towards basal levels, with a new steady state that was constant from 72h onwards. From roughly 800 spots, that were regulated comparing normoxia to chronic hypoxia, about 100 proteins were unambiguously assigned during MS/MS-analysis. Interestingly, a number of glycolytic genes were up-regulated, while a number of inner mitochondrial membrane proteins were down-regulated independently of HIF-1α or HIF-2α. Chronic hypoxic conditions depleted the mitochondrial mass by autophagy, which occurred independently of HIF proteins. Macrophages tolerate periods of chronic hypoxia very well and adaptive responses occur, at least in part, independently of HIF-1α and/or HIF-2α and comprise mitophagy as a pathway of particular importance.
    Biochimica et Biophysica Acta 10/2013; 1834(12). DOI:10.1016/j.bbapap.2013.09.023 · 4.66 Impact Factor
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    • "Virulent Holstein-Friesian (H-V) T. annulata-infected macrophages can be attenuated (H-A) by long-term culture and are used to vaccinate against tropical theileriosis. As well as promoting Warburg glycolysis, HIF induction also contributes to tumour aggressiveness due to its capacity to promote transcription of genes involved in angiogenesis, for recent reviews see (Levine and Puzio-Kuter, 2010; Koh and Powis, 2012). As H-A macrophages lose both their adhesive (Fig. 2A) and invasive capacities (Fig. 2B), we expected that these cells would exhibit decreased expression of hif-1α and hif-1β. "
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    ABSTRACT: Theileria annulata infects predominantly macrophages, and to a lesser extent B cells, and causes a widespread disease of cattle called tropical theileriosis. Disease-causing infected macrophages are aggressively invasive, but this virulence trait can be attenuated by long-term culture. Attenuated macrophages are used as live vaccines against tropical theileriosis and via their characterisation one gains insights into what host cell trait is altered concomitant with loss of virulence. We established that sporozoite infection of monocytes rapidly induces hif1-α transcription and that constitutive induction of HIF-1α in transformed leukocytes is parasite-dependent. In both infected macrophages and B cells induction of HIF-1α activates transcription of its target genes that drive host cells to perform Warburg-like glycolysis. We propose that Theileria-infected leukocytes maintain a HIF-1α-driven transcriptional programme typical of Warburg glycolysis in order to reduce as much as possible host cell H2 O2 -type oxidative stress. However, in attenuated macrophages H2 O2 production increases and HIF-1α levels consequently remained high, even though adhesion and aggressive invasiveness diminished. This indicates that Theileria infection generates a host leukocyte hypoxic response that if not properly controlled leads to loss of virulence.
    Cellular Microbiology 09/2013; 16(2). DOI:10.1111/cmi.12218 · 4.82 Impact Factor
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