José Martín-Nieto

• Ph.D. Biological Sciences
• Senior Researcher at University of Alicante

Dystroglycan (DG) is a glycoprotein composed of two subunits that remain non-covalently bound at the plasma membrane: α-DG, which is extracellular and heavily O -mannosyl glycosylated, and β-DG, an integral transmembrane polypeptide. α-DG is involved in the maintenance of tissue integrity and function in the adult, providing an O -glycosylation-dep...

Mutations in the POMT1 gene, encoding a protein O-mannosyltransferase essential for α-dystroglycan (α-DG) glycosylation, are frequently observed in a group of rare congenital muscular dystrophies, collectively known as dystroglycanopathies. However, it is hitherto unclear whether the effects seen in affected patients can be fully ascribed to α-DG h...

We have determined the effects of the IGF-1R tyrosine kinase inhibitors BMS-754807 (BMS) and OSI-906 (OSI) on cell proliferation and cell-cycle phase distribution in human colon, pancreatic carcinoma, and glioblastoma cell lines and primary cultures. IGF-1R signaling was blocked by BMS and OSI at equivalent doses, although both inhibitors exhibited...

We have previously reported the expression of Parkinson disease-associated genes encoding α-synuclein, parkin and UCH-L1 in the retina across mammals. DJ-1, or parkinsonism-associated deglycase, is a redox-sensitive protein with putative roles in cellular protection against oxidative stress, among a variety of functions, acting through distinct pat...

Hypoglycosylation of α-dystroglycan (α-DG) resulting from deficiency of protein O-mannosyltransferase 1 (POMT1) may cause severe neuromuscular dystrophies with brain and eye anomalies, named dystroglycanopathies. The retinal involvement of these disorders motivated us to generate a conditional knockout (cKO) mouse experiencing a Pomt1 intragenic de...

Hypoglycosylation of α-dystroglycan (α-DG) resulting from deficiency of protein O-mannosyltransferase 1 (POMT1) may cause severe neuromuscular dystrophies with brain and eye anomalies, named dystroglycanopathies. The retinal involvement of these disorders motivated us to generate a conditional knockout (cKO) mouse experiencing a Pomt1 intragenic de...

Purpose: Dystroglycanopathies are a heterogeneous group of recessive neuromuscular dystrophies that affect the muscle, brain and retina, and are caused by deficiencies in the O-glycosylation of α-dystroglycan. This post-translational modification is essential for the formation and maintenance of ribbon synapses in the retina. Fukutin and fukutin-re...

Purpose: Oxysterols are cholesterol-oxygenated derivatives generated in the organism and also present in foods because of cholesterol oxidation during processing and storage. They are the natural ligands of liver X receptors (LXRs) and are generally recognized as hypocholesterolemic and anti-inflammatory molecules although this latter property is...

Liver X receptors (LXRs) are ligand-activated nuclear receptors involved mainly in the regulation of cholesterol metabolism in many organs, including liver and intestine, as well as in macrophages and neutrophils. Besides, both anti-inflammatory and pro-inflammatory properties have been ascribed to LXRs. The effect of the inflammatory condition on...

Purpose: The POMGNT1 gene, encoding protein O-linked-mannose β-1,2-N-acetylglucosaminyltransferase 1, is associated with muscle-eye-brain disease (MEB) and other dystroglycanopathies. This gene's lack of function or expression causes hypoglycosylation of α-dystroglycan (α-DG) in the muscle and the central nervous system, including the brain and th...

The activity of calmodulin (CaM) is modulated not only by oscillations in the cytosolic concentration of free Ca(2+), but also by its phosphorylation status. In the present study the role of tyrosine-phosphorylated CaM (P-(Tyr)-CaM) on the regulation of the epidermal growth factor receptor (EGFR) has been examined using in vitro assay systems. We s...

El gen humano ABCA4 (=ABCR) se caracterizó en 1997 como el principal causante de la enfermedad de Stargardt, una distrofia macular hereditaria generalmente autosómica recesiva. Poco tiempo después se encontraron otras enfermedades asociadas a mutaciones en este gen, como son distrofia de conos y bastones, determinados casos de retinosis pigmentaria...

Plant crop yields are negatively conditioned by a large set of biotic and abiotic factors. An alternative to mitigate these adverse effects is the use of fungal biological control agents and endophytes. The egg-parasitic fungus Pochonia chlamydosporia has been traditionally studied because of its potential as a biological control agent of plant-par...

Regulation of liver X receptors (LXRs) is essential for cholesterol homeostasis and inflammation. The present study was conducted to determine whether oleic acid (OA) could regulate mRNA expression of LXRα and LXRα-regulated genes and to assess the potential promotion of oxidative stress by OA in neutrophils. Human neutrophils were treated with OA...

Liver X receptors (LXRs) are ligand-activated members of the nuclear receptor superfamily that regulate the expression of genes involved in lipid metabolism and inflammation, although their role in inflammation and immunity is less known. It has been described that oxysterols/LXRs may act as anti-inflammatory molecules, although opposite actions ha...

Parkinson disease is mainly characterized by the degeneration of dopaminergic neurons in the central nervous system, including the retina. Different interrelated molecular mechanisms underlying Parkinson disease-associated neuronal death have been put forward in the brain, including oxidative stress and mitochondrial dysfunction. Systemic injection...

Human neurodegenerative diseases, such as Parkinson’s disease (PD) and the neuromuscular disorders called dystroglycanopathies (DGPs), cause retinal impairments. We have used RNA-Seq technology to catalog all known genes linked to PD and DGPs expressed in the human retina. Our results show us that most of these neurodegenerative disease-related gen...

The ubiquitin-proteasome system (UPS) is the main intracellular pathway for modulated protein turnover, playing an important role in the maintenance of cellular homeostasis. It also exerts a protein quality control through degradation of oxidized, mutant, denatured, or misfolded proteins and is involved in many biological processes where protein le...

Liver X receptors (LXRs) are ligand-activated transcription factors of the nuclear receptor superfamily. They play important roles in controlling cholesterol homeostasis and as regulators of inflammatory gene expression and innate immunity, by blunting the induction of classical pro-inflammatory genes. However, opposite data have also been reported...

Saffron, an extract from Crocus sativus, has been largely used in traditional medicine for its antiapoptotic and anticarcinogenic properties. In this work, we investigate the effects of safranal, a component of saffron stigmas, in attenuating retinal degeneration in the P23H rat model of autosomal dominant retinitis pigmentosa. We demonstrate that...

Calcineurin (protein phosphatase 2B) (CN) comprises a family of serine/threonine phosphatases that play a pivotal role in signal transduction cascades in a variety of cells, including neutrophils. Angiotensin II (Ang II) increases both activity and de novo synthesis of CN in human neutrophils. This study focuses on the role that intracellular redox...

The fungi Pochonia chlamydosporia and Pochonia rubescens are parasites of nematode eggs and thus are biocontrol agents of nematodes. Proteolytic enzymes such as the S8 proteases VCP1 and P32, secreted during the pathogenesis of nematode eggs, are major virulence factors in these fungi. Recently, expression of these enzymes and of SCP1, a new putati...

To evaluate the preventive effect of tauroursodeoxycholic acid (TUDCA) on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model of autosomal dominant retinitis pigmentosa (RP). P23H line-3 rats were injected with TUDCA once a week from postnatal day (P)21 to P120, in para...

The ubiquitin-proteasome system (UPS) functions as a major degradation pathway for misfolded and damaged proteins with an important neuroprotective role in the CNS against a variety of cellular stresses. Parkin and ubiquitin C-terminal hydrolase L1 (UCH-L1) are two relevant components of the UPS associated with a number of neurodegenerative disorde...

Nematophagous fungi Pochonia chlamydosporia and P. rubescens colonize endophytically barley roots. During nematode infection, serine proteases are secreted. We have investigated whether such proteases are also produced during root colonization. Polyclonal antibodies against serine protease P32 of P. rubescens cross-reacted with a related protease (...

La presente memoria de investigación recoge los resultados del grupo de trabajo de la Red Elaboración de la guía docente de la asignatura Iniciación a la Investigación por todos los departamentos con docencia en la misma, del Proyecto Redes de Investigación en Docencia Universitaria 2010, presentado en la Modalidad I: Redes de Investigación en Doce...

In the adult mammalian brain generation of newly-formed neurons (neurogenesis) takes place in a limited fashion from neural stem cells residing in two discrete niches located in the lateral ventricle and the hippocampus. In the retina persistent neurogenesis occurs in fish and amphibians in the so-called ciliary margin zone, located in the anterior...

The adult mammalian retina has for long been considered to lack a neurogenerative capacity. However, retinal stem/progenitor cells, which can originate retinal neurons in vitro, have been recently reported in the ciliary body of adult mammals. Here we explored the possibility of retinal neurogenesis occurring in vivo in adult monkeys and humans. We...

Angiotensin II (Ang II) is a peptide hormone able to elicit a strong production of reactive oxygen species by human neutrophils. In this work, we have addressed whether expression of heme oxygenase-1 (HO-1), an antioxidant enzyme, becomes altered in these cells upon Ang II treatment or under hypertension conditions. In neutrophils from healthy and...

Descrita y bellamente ilustrada por el oftalmólogo alemán Karl Stargardt en 1909, constituye la degeneración macular genética más frecuente en seres humanos, y se estima que afecta a más de 4.000 personas en España. Su relativamente baja incidencia en comparación con otras formas de ceguera, junto al hecho de que los campos visuales periféricos gen...

Angiotensin II (Ang II) highly stimulates superoxide anion production by neutrophils. The G-protein Rac2 modulates the activity of NADPH oxidase in response to various stimuli. Here, we describe that Ang II induced both Rac2 translocation from the cytosol to the plasma membrane and Rac2 GTP-binding activity. Furthermore, Clostridium difficile toxin...

NFAT (nuclear factors of activated T cells) proteins constitute a family of transcription factors involved in mediating signal transduction. The presence of NFAT isoforms has been described in all cell types of the immune system, with the exception of neutrophils. In the present work we report for the first time the expression in human neutrophils...

Alpha-synuclein is a Parkinson's disease-linked protein of ubiquitous expression in the central nervous system. It has a proposed role in the modulation of neurotransmission and synaptic function. This study was aimed at analyzing expression of the alpha-synuclein gene in the normal retina, and characterizing its pattern of distribution in the diff...

En realidad no se trata de una enfermedad única, sino que se conoce por este nombre desde hace casi 150 años a un conjunto de degeneraciones hereditarias de la retina, muy heterogéneas tanto en sus síntomas y edad de aparición como en su base genética. Los fotorreceptores (es decir, las células sensoriales de la retina responsables de captar la luz...

Cyclooxygenase (COX) is a key enzyme in prostaglandin (PG) synthesis. Up-regulation of its COX-2 isoform is responsible for the increased PG release, taking place under inflammatory conditions, and also, is thought to be involved in allergic and inflammatory diseases. In the present work, we demonstrate that COX-2 expression becomes highly induced...

Physiological abnormalities resulting from death of dopaminergic neurons of the central nervous system in Parkinson's disease also extend to the retina, resulting in impaired visual functions. In both parkinsonian patients and animal models, low levels of dopamine and loss of dopaminergic cells in the retina have been reported. However, the morphol...

Estudios electrofisiológicos y psicofísicos han revelado anomalías en las funciones visuales retinianas asociadas a la enfermedad de Parkinson. Hemos generado una situación de Parkinson experimental en monos mediante la administración del neurotóxico MPTP, el cual destruye selectivamente las neuronas dopaminérgicas, y evaluado su efecto sobre los d...

This report focuses on the modulatory role of endogenous H(2)O(2) on lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-induced inducible nitric oxide synthase (NOS2) gene expression in rat peritoneal macrophages. Exogenously added H(2)O(2) was initially found to inhibit the synthesis of NOS2, which prompted us to assess the effect of the activi...

15-Deoxy-Δ12,14-prostaglandin J2 (15dPGJ2 has been recently proposed as a potent anti-inflammatory agent. However, the mechanisms by which 15dPGJ2 mediates its therapeutic effects in vivo are unclear. We demonstrate that 15dPGJ2 at micromolar (2.5–10 μm) concentrations induces the expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme,...

Hyperhomocysteinaemia has recently been recognized as a risk factor of cardiovascular disease. However, the action mechanisms of homocysteine (Hcy) are not well understood. Given that Hcy may be involved in the recruitment of monocytes and neutrophils to the vascular wall, we have investigated the role of Hcy in essential functions of human neutrop...

Neutrophils are mobilized to the vascular wall during vessel inflammation. Published data are conflicting on phagocytic nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activation during the hypertensive state, and the capacity of angiotensin II (Ang II) to modulate the intracellular redox status has not been analyzed in neutrophils. We...

The mechanisms underlying the bactericidal power of fluoroquinolones against intracellular parasites in host macrophages remain poorly understood. We have analyzed the effect of norfloxacin, a fluoroquinolone antibiotic, on the production of reactive oxygen intermediates (O(2)(*-) and H(2)O(2)) and NADPH oxidase activity in mouse macrophages. The g...

We have identified in plasma membrane fractions isolated from rat hepatocarcinoma AS-30D ascites cells three glycoproteins of 125 kDa, 115 kDa and 105 kDa (gp125, gp115 and gp105) which become adenylylated using ATP as substrate, most readily in the presence of EDTA. The gp115 becomes also phosphorylated. The adenylylation of these tumor glycoprote...

Signal transduction by two-component regulatory systems involves phosphorylation of the receiver domain of a response regulator by the transmitter domain of the cognate histidine kinase. In the NtrBC system, phosphorylation of NtrC by NtrB results in transcriptional activation of nitrogen-regulated genes. We have used the yeast two-hybrid system to...

Although the brain is an important target for the human immunodeficiency virus type 1 (HIV) and viral infection causes neuronal degeneration and dementia, the mechanisms responsible for HIV transcription in neuronal cells are largely unknown. We show here that retinoic acid (RA) stimulates HIV transcription in human neuronal SH-SY5Y cells. The ster...

A rise in intracellular Ca(2+) levels has been implicated as a regulatory signal for the initiation of lymphocyte proliferation. In the present study the mechanism underlying the elevation of [Ca(2+)] induced by phenylarsine oxide [PAO] was investigated in thymocytes. This agent inhibits HIV-1 replication and also NF-kappaB-mediated activation. It...

Oxidizing agents are powerful activators of factors responsible for the transcriptional activation of cytokine-encoding genes involved in tissue injury. In this study we show evidence that STAT3 is a transcription factor whose activity is modulated by H2O2 in human lymphocytes, in which endogenous catalase had previously been inhibited. H2O2-induce...

We describe here a specific calcineurin activity in neutrophil lysates, which is dependent on Ca2+, inhibited by trifluoroperazine, and insensitive to okadaic acid. Immunoblotting experiments using a specific antiserum recognized both the A and B chains of calcineurin. Neutrophils treated with cyclosporin A or FK 506 showed a dose-dependent inhibit...

Concentration-dependence data for nitrate reductase (EC 1.7.99.4) from heterocystous, nitrogen-fixing cyanobacteria (J. Martín-Nieto, E. Flores and A. Herrero, 1992. Plant Physiol. 100: 157–163) have been interpreted most plausibly to reflect the operation of a single enzyme with two independent catalytic sites. However, data from a total of 30 exp...

A ligand-insensitive form of the human epidermal growth factor receptor (EGFR) was enriched by Ca2+-dependent calmodulin-affinity chromatography purification. The basic amphiphilic segment Arg645-Arg-Arg-His-Ile-Val-Arg-Lys-Arg-Thr654-Leu-Arg-Arg-Le u-Leu-Gln 660, located within the cytoplasmic juxtamembrane domain of this receptor, was purified as...

Gap junctions are organized as clusters of multiple head-to-head hexameric channels from adjacent cells directly communicating their cytosols. These structures mediate the passage of ions, metabolites and second messengers of low molecular mass (< 1-1.2 kDa) among cells in the tissues. Thus, they allow the synchronization of cellular activities inc...

Although it has been demonstrated that NO inhibits the proliferation of different cell types, the mechanisms of its anti-mitotic action are not well understood. In this work we have studied the possible interaction of NO with the epidermal growth factor receptor (EGFR), using transfected fibroblasts which overexpress the human EGFR. The NO donors S...

Previously we described a large collection of cloned human DNAs that encode chemically defined missense mutations within the ribosomal protein S14 sequence. We determined that biologically inactive (i.e. null) alleles resulted primarily from point mutations targeted to two internal segments of the S14-coding sequence and designated these functional...

Ehrlich ascites tumor cells incorporate [methyl-3H]thymidine into DNA independently of exogenous growth factors or fetal calf serum. Using an acid/ethanol extraction procedure we have obtained from these tumor cells a fraction that induces both the proliferation and the formation of cell foci by Swiss 3T3 mouse fibroblasts in the presence of insuli...

Detergent-permeabilized EGFR-T17 fibroblasts, which overexpress the human epidermal growth factor (EGF) receptor, phosphorylate both poly-L-(glutamic acid, tyrosine) and exogenous calmodulin in an EGF-stimulated manner. Phosphorylation of calmodulin requires the presence of cationic polypeptides, such as poly-L-(lysine) or histones, which exert a b...

The ntcA gene from Synechococcus sp. strain PCC 7942 encodes a regulatory protein which is required for the expression of all of the genes known to be subject to repression by ammonium in that cyanobacterium. Homologs to ntcA have now been cloned by hybridization from the cyanobacteria Synechocystis sp. strain PCC 6803 and Anabaena sp. strain PCC 7...

Nitrate reductase activity from filamentous, heterocyst-forming cyanobacteria showed a biphasic kinetic behavior with respect to nitrate as the variable substrate. Two kinetic components were detected, the first showing a higher affinity for nitrate (K(m), 0.05-0.25 mm) and a lower catalytic activity and the second showing a lower affinity for nitr...

Presentada en el año 1991 como Tesis Doctoral Incluye bibliografía e índice

Nitrate inhibited nitrogenase synthesis and heterocyst development in the cyanobacterium Anabaena sp. strain PCC 7120. Inhibition of dinitrogen fixation by nitrate did not take place, however, in nitrate reductase-deficient derivatives of this strain. Hybridization of total RNA isolated from cells grown on different nitrogen sources with an interna...

Mutants of the dinitrogen-fixing cyanobacterium Anabaena variabilis have been isolated which are unable to synthesize active nitrate reductase under normal, low-molybdenum growth conditions. One of the mutants was also impaired in nitrogenase activity. Both deficiencies were restorable by the addition of high levels of molybdate to the medium. The...

Cyanobacteria are prokaryotic organisms that carry out oxygenic photosynthesis and are able to utilize nitrate, nitrite or ammonium as a nitrogen source for growth. Some of their representatives are also able to fix dinitrogen or to grow on certain amino acids. Although significant information is currently available concerning the physiology of nit...

The effect of the nitrogen source on nitrate reductase and nitrite reductase synthesis has been studied in several filamentous dinitrogen-fixing cyanobacteria belonging to the genera Anabaena, Nostoc and Calothrix. Nitrate and nitrite uptake were also studied. High levels of both nitrate reductase and nitrite reductase were found only in the presen...