HIF-1 and HIF-2: Working alone or together in hypoxia?

Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Journal of Clinical Investigation (Impact Factor: 13.22). 04/2007; 117(4):862-5. DOI: 10.1172/JCI31750
Source: PubMed


Erythropoietin (EPO) is the hormonal regulator of red cell production and provided the paradigm for oxygen-regulated gene expression that led to the discovery of hypoxia-inducible factor (HIF). In this issue of the JCI, Rankin and colleagues show, using targeted gene inactivation, that induction of Epo expression in murine liver is dependent on the integrity of HIF-2alpha, and not HIF-1alpha (see the related article beginning on page 1068). These results demonstrate distinct functions for different HIF-alpha isoforms that could potentially be exploited in therapeutic approaches to anemia.

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    • "The physiological response to hypoxia is stabilization of hypoxia-inducible factor (HIF)-1α and HIF-2α, which will dimerize with the β subunit and via binding to hypoxia responsive elements adapt the cell to low oxygen levels (7). HIF-1α and HIF-2α upregulate the transcription of a multitude of cytokines and growth factors (8, 9), but the two transcription factors induce expression of different proteins (10). One of the HIF-regulated proteins is the pleiotropic cytokine erythropoietin (EPO) mainly regulated by HIF-2α (11). "
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    ABSTRACT: The pathogenesis of cerebral malaria (CM) includes compromised microvascular perfusion, increased inflammation, cytoadhesion, and endothelial activation.These events cause blood–brain barrier disruption and neuropathology and associations with the vascular endothelial growth factor (VEGF) signaling pathway have been shown. We studied this pathway in mice infected with Plasmodium berghei ANKA causing murine CM with or without the use of erythropoietin (EPO) as adjunct therapy. ELISA andwestern blottingwas used for quantification of VEGF and relevant proteins in brain and plasma. CM increased levels ofVEGF in brain and plasma and decreased plasma levels of solubleVEGF receptor 2. EPO treatment normalizedVEGF receptor 2 levels and reduced brainVEGF levels. Hypoxiainducible factor (HIF)-1a was significantly upregulated whereas cerebral HIF-2a and EPO levels remained unchanged. Furthermore, we noticed increased caspase-3 and calpain activity in terminally ill mice, as measured by protease-specific cleavage of a-spectrin and p35. In conclusion, we detected increased cerebral and systemic VEGF as well as HIF-1a, which in the brain were reduced to normal in EPO-treated mice. Also caspase and calpain activity was reduced markedly in EPO-treated mice.
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    • "Three a subunits have been identified: HIF-1a, HIF-2a, and HIF-3a, with HIF-1a and HIF-2a being the most extensively characterized (Keith et al., 2012). Despite sharing a high degree of sequence identity, HIF-1a and HIF-2a are not redundant, because they are expressed at least partly in a tissue-specific manner and regulate a number of unique target genes (Ratcliffe, 2007; Keith et al., 2012). In hypoxic conditions, HIF transcription factors trigger a variety of adaptive responses that include induction of anaerobic metabolism, cell migration, and neo-angiogenesis (Semenza, 2003). "
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    ABSTRACT: Maintenance and differentiation of hematopoietic stem cells (HSCs) is regulated through cell-autonomous and non-cell-autonomous mechanisms within specialized bone marrow microenvironments. Recent evidence demonstrates that signaling by HIF-1α contributes to cell-autonomous regulation of HSC maintenance. By investigating the role of HIF factors in bone marrow mesenchymal progenitors, we found that murine endosteal mesenchymal progenitors express high levels of HIF-1α and HIF-2α and proliferate preferentially in hypoxic conditions ex vivo. Inactivation of either HIF-1α or HIF-2α dramatically affects their phenotype, propagation, and differentiation. Also, downregulation of HIF factors provokes an increase in interferon-responsive genes and triggers expansion and differentiation of hematopoietic progenitors by a STAT1-mediated mechanism. Interestingly, in conditions of demand-driven hematopoiesis HIF factors are specifically downregulated in mesenchymal progenitors in vivo. In conclusion, our findings indicate that HIF factors also regulate hematopoiesis non-cell-autonomously by preventing activation of a latent program in mesenchymal progenitors that promotes hematopoiesis.
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    • "Also HIF2α and HIF3α present hypoxic stabilization and binding to HIF1β although with different kinetics. Both HIF2α and HIF3α appear expressed in a cell-specific manner and play non redundant roles in adapting to hypoxia and in hypoxic tumor growth and progression [14], [15]. Increasing evidence indicates that the inflammatory microenvironment is a further contributing factor leading to cancer development in the prostate [16], [17]. "
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    ABSTRACT: Hypoxia and inflammation are strictly interconnected both concurring to prostate cancer progression. Numerous reports highlight the role of tumor cells in the synthesis of pro-inflammatory molecules and show that hypoxia can modulate a number of these genes contributing substantially to the increase of cancer aggressiveness. However, little is known about the importance of the tumor phenotype in this process. The present study explores how different features, including differentiation and aggressiveness, of prostate tumor cell lines impact on the hypoxic remodeling of pro-inflammatory gene expression and malignancy. We performed our studies on three cell lines with increasing metastatic potential: the well differentiated androgen-dependent LNCaP and the less differentiated and androgen-independent DU145 and PC3. We analyzed the effect that hypoxic treatment has on modulating pro-inflammatory gene expression and evaluated the role HIF isoforms and NF-kB play in sustaining this process. DU145 and PC3 cells evidenced a higher normoxic expression and a more complete hypoxic induction of pro-inflammatory molecules compared to the well differentiated LNCaP cell line. The role of HIF1α and NF-kB, the master regulators of hypoxia and inflammation respectively, in sustaining the hypoxic pro-inflammatory phenotype was different according to cell type. NF-kB was observed to play a main role in DU145 and PC3 cells in which treatment with the NF-kB inhibitor parthenolide was able to counteract both the hypoxic pro-inflammatory shift and HIF1α activation but not in LNCaP cells. Our data highlight that tumor prostate cell phenotype contributes at a different degree and with different mechanisms to the hypoxic pro-inflammatory gene expression related to tumor progression.
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