Publications (5)30.78 Total impact
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Article: Prolyl hydroxylase-dependent modulation of eukaryotic elongation factor 2 activity and protein translation under acute hypoxia.
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ABSTRACT: Early adaptive responses to hypoxia are essential for cell survival, but their nature and underlying mechanisms are poorly known. We have studied the post-transcriptional changes in the proteome of mammalian cells elicited by acute hypoxia and found that phosphorylation of eukaryotic elongation factor 2 (eEF2), a ribosomal translocase whose phosphorylation inhibits protein synthesis, is under the precise and reversible control of O(2) tension. Upon exposure to hypoxia, phosphorylation of eEF2 at Thr(56) occurred rapidly (<15 min) and resulted in modest translational arrest, a fundamental homeostatic response to hypoxia that spares ATP and thus facilitates cell survival. Acute inhibitory eEF2 phosphorylation occurred without ATP depletion or AMP kinase activation. Furthermore, eEF2 phosphorylation was mimicked by prolyl hydroxylase (PHD) inhibition with dimethyloxalylglycine or by selective PHD2 siRNA silencing but was independent of hypoxia-inducible factor α stabilization. Moreover, overexpression of PHD2 blocked hypoxic accumulation of phosphorylated eEF2. Therefore, our findings suggest that eEF2 phosphorylation status (and, as a consequence, translation rate) is controlled by PHD2 activity. They unravel a novel pathway for cell adaptation to hypoxia that could have pathophysiologic relevance in tissue ischemia and cancer.Journal of Biological Chemistry 02/2012; 287(12):9651-8. · 4.77 Impact Factor -
Article: GDNF and protection of adult central catecholaminergic neurons.
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ABSTRACT: Neurotrophic factors are small proteins necessary for neuron survival and maintenance of phenotype. They are considered as promising therapeutic tools for neurodegenerative diseases. The glial cell line-derived neurotrophic factor (GDNF) protects catecholaminergic cells from toxic insults; thus, its potential therapeutic applicability in Parkinson's disease has been intensely investigated. In recent years, there have been major advances in the analysis of GDNF signaling pathways in peripheral neurons and embryonic dopamine mesencephalic cells. However, the actual physiological role of GDNF in maintaining catecholaminergic central neurons during adulthood is only starting to be unraveled, and the mechanisms whereby GDNF protects central brain neurons are poorly known. In this study, we review the current knowledge of GDNF expression, signaling, and function in adult brain, with special emphasis on the genetic animal models with deficiency in the GDNF-dependent pathways.Journal of Molecular Endocrinology 02/2011; 46(3):R83-92. · 3.48 Impact Factor -
Article: Oxygen sensing in the carotid body.
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ABSTRACT: The carotid body (CB) is a neural crest-derived organ whose function is to elicit hyperventilation in response to hypoxemia. The CB contains clusters of neuron-like glomus cells enveloped by glia-like sustentacular cells. CB responsiveness to acute hypoxia relies on the inhibition of O2-sensitive K+ channels in glomus cells, which leads to depolarization, Ca2+ entry and release of transmitters that activate afferent nerve fibers. The molecular mechanisms underlying K+ channel modulation by O2 tension are unknown. Putative hypoxia-sensing mechanisms can be studied in detail using genetically modified mice in conjunction with a thin carotid body slice preparation. We discuss here the role in CB oxygen sensing of the hypoxia-inducible factor 1alpha, the mitochondrial complex II subunit D, and heme oxygenase 2. In chronic hypoxia the CB grows with increase in glomus cell number. We identified CB stem cells of glial lineage, which can differentiate into functionally normal glomus cells.Annals of the New York Academy of Sciences 10/2009; 1177:119-31. · 3.15 Impact Factor -
Article: Absolute requirement of GDNF for adult catecholaminergic neuron survival.
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ABSTRACT: GDNF is a potent neurotrophic factor that protects catecholaminergic neurons from toxic damage and induces fiber outgrowth. However, the actual role of endogenous GDNF in the normal adult brain is unknown, even though GDNF-based therapies are considered promising for neurodegenerative disorders. We have generated a conditional GDNF-null mouse to suppress GDNF expression in adulthood, hence avoiding the developmental compensatory modifications masking its true physiologic action. After Gdnf ablation, mice showed a progressive hypokinesia and a selective decrease of brain tyrosine hydroxylase (Th) mRNA, accompanied by pronounced catecholaminergic cell death, affecting most notably the locus coeruleus, which practically disappears; the substantia nigra; and the ventral tegmental area. These data unequivocally demonstrate that GDNF is indispensable for adult catecholaminergic neuron survival and also show that, under physiologic conditions, downregulation of a single trophic factor can produce massive neuronal death.Nature Neuroscience 08/2008; 11(7):755-61. · 15.53 Impact Factor -
Article: Acute oxygen sensing in heme oxygenase-2 null mice.
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ABSTRACT: Hemeoxygenase-2 (HO-2) is an antioxidant enzyme that can modulate recombinant maxi-K(+) channels and has been proposed to be the acute O(2) sensor in the carotid body (CB). We have tested the physiological contribution of this enzyme to O(2) sensing using HO-2 null mice. HO-2 deficiency leads to a CB phenotype characterized by organ growth and alteration in the expression of stress-dependent genes, including the maxi-K(+) channel alpha-subunit. However, sensitivity to hypoxia of CB is remarkably similar in HO-2 null animals and their control littermates. Moreover, the response to hypoxia in mouse and rat CB cells was maintained after blockade of maxi-K(+) channels with iberiotoxin. Hypoxia responsiveness of the adrenal medulla (AM) (another acutely responding O(2)-sensitive organ) was also unaltered by HO-2 deficiency. Our data suggest that redox disregulation resulting from HO-2 deficiency affects maxi-K(+) channel gene expression but it does not alter the intrinsic O(2) sensitivity of CB or AM cells. Therefore, HO-2 is not a universally used acute O(2) sensor.The Journal of General Physiology 11/2006; 128(4):405-11. · 3.84 Impact Factor
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Institutions
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2006–2011
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Universidad de Sevilla
- Instituto de Biomedicina de Sevilla (IBIS)
Sevilla, Andalusia, Spain
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