Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ectopic expression of the doppel (Dpl) protein, a homologue of the prion protein (PrP), was recently associated with cerebellar Purkinje cell degeneration observed in two aging prion protein knock-out (Prnp(0/0)) mouse lines. We investigated the possible role of Dpl in oxidative metabolism. Two Prnp(0/0) mouse lines of similar genetic background were studied. One line expresses Dpl in the brain and displays Dpl-associated cerebellar abnormalities. The other has no elevated expression of Dpl and no cerebellar abnormalities. We observed a correlation between Dpl expression and the induction of both heme oxygenase 1 (HO-1) and nitric oxide synthase systems (nNOS and iNOS). These responses are suggestive of increased oxidative stress in the brains of the Dpl-expressing Prnp(0/0) mice. No induction was observed with Hsp-60, indicating a specific response by the HO/NOS system. We proposed that Dpl expression exacerbates oxidative damage that is antagonistic to the protective function of wild-type PrP.
Mol Cell Neurosci 2001 Apr
PMID:Induction of HO-1 and NOS in doppel-expressing mice devoid of PrP: implications for doppel function. 1131 11

Methamphetamine (METH)-induced alterations in the expression of p53 and bcl-2 protein were studied in the striatum of wild type, neuronal nitric oxide synthase knockout (nNOS -/-) and copper zinc superoxide dismutase overexpressed (SOD-Tg) mice. METH treatment up-regulated p53 and down-regulated bcl-2 expression in the striatum of wild type mice. No significant alterations were observed in the expression of these proteins in the nNOS -/- or SOD-Tg mice. These data suggest that METH might cause its neurotoxic effects via the production of free radicals and secondary perturbations in the expression of genes known to be involved in apoptosis and cell death machinery.
Brain Res Mol Brain Res 2001 Jul 13
PMID:Methamphetamine-induced alteration in striatal p53 and bcl-2 expressions in mice. 1145 7

DOPA responsive dystonia (DRD) and sepiapterin reductase (SR) deficiency are inherited disorders of tetrahydrobiopterin (BH4) metabolism characterized by the signs and symptoms related to monoamine neurotransmitter deficiency. In contrast to classical forms of BH4 deficiency DRD and SR deficiency present without hyperphenylalaninemia and thus cannot be detected by the neonatal screening for phenylketonuria (PKU). While DRD is mostly caused by autosomal dominant mutations in the GTP cyclohydrolase I gene (GCH1), SR deficiency is an autosomal recessive disease. The most important biochemical investigations for the diagnosis of these neurological diseases includes CSF investigations for neurotransmitter metabolites and pterins as well as neopterin and biopterin production in cytokine-stimulated fibroblasts. Discovery of SR deficiency opened new insights into alternative pathways of the cofactor BH4 via carbonyl, aldose, and dihydrofolate reductases. As a consequence of the low dihydrofolate reductase activity in the brain, dihydrobiopterin intermediate accumulates and inhibits tyrosine and tryptophan hydroxylases and uncouples nitric oxide synthase (nNOS), leading to neurotransmitter deficiency and possibly also to neuronal cell death.
Mol Genet Metab
PMID:Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency. 1159 14

Activation of p38 mitogen-activated protein kinase (p38 MAPK) has been implicated in pathological changes in inflammatory and apoptotic processes in various cell types including neurons. Here we report the delayed induction of p38 MAPKs in the brain of mice following kainic acid (KA)-induced seizure. The immunoreactivities of p38alpha and p38beta MAPKs were markedly increased in the brain 4 days after KA administration, especially in the areas undergoing selective neuronal loss. In particular, p38beta was dramatically increased in reactive astrocytes of CA3 and CA1 regions of hippocampus with its enriched localization in the nucleus of astrocytes. The induction of p38beta was sustained for more than 10 days after KA-treatment. Pre-administration of the selective neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI), which suppressed the delayed neuronal death as well as astrogliosis in hippocampus of seizure-experienced animals, dramatically repressed the delayed induction of p38beta MAPK in astrocytes. The repression was reversed by the co-injection with L-arginine (L-arg), a substrate for NOS, which coincided with the aggravation of neuronal death. Together, these data suggested a role of p38 MAPK signal pathway in delayed neuronal death and/or in reactive gliosis in mice with KA-induced seizure.
Brain Res Mol Brain Res 2001 Oct 19
PMID:Delayed induction of p38 MAPKs in reactive astrocytes in the brain of mice after KA-induced seizure. 1159 76

Spinal cord tissue contains two enzyme systems capable of producing monoxide gases which in turn are linked to the stimulation of soluble guanylate cyclase, nitric oxide synthase (NOS) which produces NO and heme oxygenase (HO) which produces CO. Reports from several laboratories link these two enzyme systems to pain of inflammatory and neuropathic etiologies. Additional studies have demonstrated that the activation of the NOS system by morphine limits the spinal analgesic action of this drug. In this study we first employed the hot plate model of pain to demonstrate that the NOS inhibitor L-NAME and the HO inhibitor Sn-P potentiate the analgesic actions of intrathecally administered morphine while having no intrinsic analgesic action at the doses used. We then determined that L-NAME loses its ability to potentiate morphine in nNOS null-mutant mice, while Sn-P no longer potentiates morphine in mice lacking a functional HO-2 gene. The intrathecal injection of the cGMP analog 8-Br cGMP caused hyperalgesia in the hot plate assay. Focusing on the possible involvement of cGMP metabolism, we documented that morphine stimulates cGMP production in a spinal cord slice model in a concentration dependent and naloxone reversible manner. Both L-NAME and Sn-P were potent inhibitors of morphine-stimulated cGMP production. Buffer containing either CO or the NO donor compound SNAP stimulated cGMP production as well. In spinal cord slices from either nNOS or HO-2 null-mutant animals morphine did not stimulate cGMP production. Taken together our data suggest that spinal monoxide generation modifies the acute analgesic actions of morphine.
Brain Res Mol Brain Res 2001 Nov 01
PMID:Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia. 1168 80

The devastating muscle degeneration characteristic of Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. The dystrophin complex has two functions: a structural role in maintaining sarcolemmal integrity during contraction and a scaffolding function that recruits signaling proteins such as neuronal nitric oxide synthase to the membrane. New studies indicate that transgenic restoration of nitric oxide (NO) production in the mdx dystrophic mouse improves muscle pathology. Although NO-mediated killing of inflammatory cells might be involved, other mechanisms are also possible. These results point to the therapeutic potential of manipulating the signaling activity of the dystophin complex as a way to ameliorate the progression of muscle degeneration.
Trends Mol Med 2002 Feb
PMID:Just say NO to muscle degeneration? 1181 64

Modification of tyrosine residues and formation of 3-nitrotyrosine is one of the most commonly identified effects of reactive nitrogen species on proteins. In this study we evaluated the presence and localization of tyrosine nitration in various ventilatory and limb muscles. We also assessed the contribution of the neuronal (nNOS), the endothelial (eNOS), and the inducible (iNOS) isoforms of nitric oxide synthase (NOS) to tyrosine nitration in skeletal muscles both under normal conditions and in response to severe sepsis. In normal rats and mice, muscle tyrosine nitration was detected at 52, 48, 40, 30, 18, and 10 kD protein bands. Tyrosine nitration of the majority of these protein bands was significantly reduced within 1 h of in vivo NOS inhibition in rats. Diaphragmatic protein tyrosine nitration in mice deficient in the inducible NOS (iNOS-/-) averaged ~ 50% of that detected in wild-type (iNOS+/+) mice. Injection of bacterial lipopolysaccharides (LPS) in rats produced a significant rise in protein tyrosine nitration in the mitochondrial and membrane fractions but not in the cytosol of ventilatory muscles. Absence of iNOS expression (iNOS-/-), but not nNOS (nNOS-/-) or eNOS (eNOS-/-), in genetically altered mice resulted in a significant reduction in LPS-mediated rise in diaphragmatic nitrotyrosine. We conclude that tyrosine nitration of proteins occurs in normal muscle fibers and is dependent mainly on the activity of the iNOS isoform. Sepsis-mediated increase in protein tyrosine nitration is limited to the mitochondria and cell membrane and is highly dependent on the activity of the iNOS but not the nNOS or eNOS isoforms.
Am J Respir Cell Mol Biol 2002 Apr
PMID:Protein tyrosine nitration in the ventilatory muscles: role of nitric oxide synthases. 1191 80

Protein kinase A (PKA) and neuronal nitric oxide synthase (nNOS) are important signaling molecules. It is well known that PKA can specifically phosphorylate nNOS. But the underlying molecular mechanism is still obscure. Our data indicate that the protein inhibitor of nNOS (PIN) binds to protein kinase A inhibitors (PKIs), which suggests that PKIs, together with PIN, might mediate the phosphorylation of nNOS by PKA.
Brain Res Mol Brain Res 2002 Mar 28
PMID:Protein inhibitor of neuronal nitric oxide synthase interacts with protein kinase A inhibitors. 1197 6

Pulsed electromagnetic field (PEMF) has been shown to improve the rate of peripheral nerve regeneration. In the present study we investigated the expression of neuronal nitric oxide synthase (nNOS) and phospholipase C-gamma1 (PLC-gamma1) in regenerating rat laryngeal nerves during the exposure to PEMF after surgical transection and reanastomosis. Axons were found to regenerate into the distal stump nearly twice faster in PEMF-exposed animals than in the control. Consistently, motor function was better recovered in PEMF-treated rats. The expression of nNOS and PLC-gamma1 was highly enhanced in the regenerated nerves.
Exp Mol Med 2002 Mar 31
PMID:Enhanced expression of neuronal nitric oxide synthase and phospholipase C-gamma1 in regenerating murine neuronal cells by pulsed electromagnetic field. 1198 79

DNA inversions are mutations involving major rearrangements of the genome and are often regarded as either deleterious or catastrophic to gene function and can be associated with genomic disorders, such as Hunter syndrome and some forms of hemophilia. Here, we propose that DNA inversions are also an essential and hitherto unrecognized component of gene evolution in eukaryotic cells. Specifically, we provide evidence that an ancestral neuronal nitric oxide synthase (nNOS) gene was duplicated and that one copy retained its original function, whereas an internal DNA inversion occurred in the other. Crucially, the inversion resulted in the creation of new regulatory elements required for the termination and activation of transcription. In consequence, the duplicated gene was split, and two new and independently expressed genes were created. Through its dependence on DNA inversion, this is a fundamentally new scheme for gene evolution, which we show as being of particular relevance to the generation of endogenous antisense-containing RNA molecules. Functionally, such transcripts can operate as natural negative regulators of the expression of the genes to which they are related through a common ancestor.
Mol Biol Evol 2002 Aug
PMID:Evolution of nitric oxide synthase regulatory genes by DNA inversion. 1214 Feb 34


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