Calcium signaling stimulates translation of ΗΙF-α during hypoxia

Department of Genome Science, Genome Research Institute, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0505, USA.
The FASEB Journal (Impact Factor: 5.48). 04/2006; 20(3):466-75. DOI: 10.1096/fj.05-5086com
Source: PubMed

ABSTRACT Hypoxia-inducible factors (HIFs) are ubiquitous transcription factors that mediate adaptation to hypoxia by inducing specific sets of target genes. It is well accepted that hypoxia induces accumulation and activity of HIFs by causing stabilization of their alpha subunits. We have demonstrated that hypoxia stimulates translation of HIF-1alpha and -2alpha proteins by distributing HIF-alpha mRNAs to larger polysome fractions. This requires influx of extracellular calcium, stimulation of classical protein kinase C-alpha (cPKC-alpha), and the activity of mammalian target of rapamycin, mTOR. The translational component contributes to approximately 40-50% of HIF-alpha proteins accumulation after 3 h of 1% O2. Hypoxia also inhibits general protein synthesis and mTOR activity; however, cPKC-alpha inhibitors or rapamycin reduce mTOR activity and total protein synthesis beyond the effects of hypoxia alone. These data show that during general inhibition of protein synthesis by hypoxia, cap-mediated translation of selected mRNAs is induced through the mTOR pathway. We propose that calcium-induced activation of cPKC-alpha hypoxia partially protects an activity of mTOR from hypoxic inhibition. These results provide an important physiologic insight into the mechanism by which hypoxia-stimulated influx of calcium selectively induces the translation of mRNAs necessary for adaptation to hypoxia under conditions repressing general protein synthesis.

    • "Both ROS and Ca 2+ are important signaling molecules that regulate the response to hypoxia. Ca 2+ modulates cell contraction, cell proliferation and growth (Shimoda and Undem 2010; Wang and Zheng 2010), and calcium signaling will stimulate the translation of HIF-alpha, an ubiquitous transcription factors that mediates adaptation to hypoxia (Hui et al. 2006) (fig. 4). "
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    ABSTRACT: Much like other indigenous domesticated animals, Tibetan chickens living at high altitudes (2,200~4,100 m) show specific physiological adaptations to the extreme environmental conditions of the Tibetan Plateau, but the genetic bases of these adaptations are not well characterized. Here, we assembled a de novo genome of a Tibetan chicken, and re-sequenced whole genomes of 32 additional chickens, including Tibetan chickens, village chickens, game fowl, and Red Junglefowl, and found that the Tibetan chickens could broadly be placed into two groups. Further analyses revealed that several candidate genes in the calcium-signaling pathway are possibly involved in adaptation to the hypoxia experienced by these chickens, as these genes appear to have experienced directional selection in the two Tibetan chicken populations, suggesting a potential genetic mechanism underlying high altitude adaptation in Tibetan chickens. The candidate selected genes identified in this study, and their variants, may be useful targets for clarifying our understanding of the domestication of chickens in Tibet, and might be useful in current breeding efforts to develop improved breeds for the highlands. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail:
    Molecular Biology and Evolution 03/2015; 32(7). DOI:10.1093/molbev/msv071 · 14.31 Impact Factor
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    • "Increasing evidence suggests that hyperglycemia induces changes in the retinal [Ca2+]i dynamics2,4, which have been associated with distinct pathological processes, such as DR. Here, using retinal Müller cells cultured in vitro, we have demonstrated that the increased [Ca2+]i is associated with aberrant HG-induced expression of HIF-1α and VEGF because increased [Ca2+]i is an ubiquitous signal controlling gene expression9,10,29,30. We evaluated HG-induced HIF-1α and VEGF expression in the presence of pharmacologic inhibitors of Ca2+ signaling. "
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    ABSTRACT: To investigate the effects of high glucose (HG) medium on expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in cultured rat retinal Müller cells and to determine the signaling pathways mediating the effects. Primary cultures of retinal Müller cells were prepared from Sprague-Dawley rats, and incubated in a medium containg HG (30 mmol/L) in the presence of the membrane-permeable Ca(2+) chelator BAPTA-AM (10 μmol/L) or the CaMKII inhibitor KN93 (10 μmol/L). The levels of CaMKII, p-CaMKII, CREB, p-CREB, HIF-1α, and VEGF proteins were measured with Western blotting, while HIF-1á and VEGF mRNA levels were determined using real-time RT-PCR. The stimulation of retinal Müller cell with HG for 24 h remarkably increased the expression levels of HIF-1α and VEGF. These responses were significantly inhibited in the presence of BAPTA-AM or KN93. Both BAPTA-AM and KN93 also significantly inhibited HG-induced phosphorylation of CaMKII and CREB in the cultured retinal Müller cells. Transfection of the cultured retinal Müller cells with antisense CREB oligonucleotide (300 nmol/L) was similarly effective in blocking the HG-induced increase of HIF-1α and VEGF. HG-induced HIF-1α and VEGF expression in cultured rat retinal Müller cells depends on intracellular free Ca(2+) and activation of CaMKII-CREB pathway. The activation of CaMKII-CREB pathway by HG may be a possible mechanism underlying the pathogenesis of diabetic retinopathy.
    Acta Pharmacologica Sinica 07/2012; 33(8):1030-6. DOI:10.1038/aps.2012.61 · 2.50 Impact Factor
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    • "For example, protein kinase C (PKC) [50], mitogen-activating protein kinases (MAPKs) [51], and reactive oxygen species (ROS) [52] are modulated by anesthetics. PKC, MAPK, and ROS are also identified to affect HIF activity by modulating HIF-α protein translation rate, hydroxylation, and phosphorylation of HIF-α protein [53], [54], [55]. Therefore, general anesthetics may affect astrocytes through modulation of such enzymes and mediators. "
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    ABSTRACT: Erythropoietin (EPO), originally identified as a hematopoietic growth factor produced in the kidney and fetal liver, is also endogenously expressed in the central nervous system (CNS). EPO in the CNS, mainly produced in astrocytes, is induced under hypoxic conditions in a hypoxia-inducible factor (HIF)-dependent manner and plays a dominant role in neuroprotection and neurogenesis. We investigated the effect of general anesthetics on EPO expression in the mouse brain and primary cultured astrocytes. BALB/c mice were exposed to 10% oxygen with isoflurane at various concentrations (0.10-1.0%). Expression of EPO mRNA in the brain was studied, and the effects of sevoflurane, halothane, nitrous oxide, pentobarbital, ketamine, and propofol were investigated. In addition, expression of HIF-2α protein was studied by immunoblotting. Hypoxia-induced EPO mRNA expression in the brain was significantly suppressed by isoflurane in a concentration-dependent manner. A similar effect was confirmed for all other general anesthetics. Hypoxia-inducible expression of HIF-2α protein was also significantly suppressed with isoflurane. In the experiments using primary cultured astrocytes, isoflurane, pentobarbital, and ketamine suppressed hypoxia-inducible expression of HIF-2α protein and EPO mRNA. Taken together, our results indicate that general anesthetics suppress activation of HIF-2 and inhibit hypoxia-induced EPO upregulation in the mouse brain through a direct effect on astrocytes.
    PLoS ONE 12/2011; 6(12):e29378. DOI:10.1371/journal.pone.0029378 · 3.23 Impact Factor
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