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

Disorders of the central nervous system are a major concern in modern human societies. Studies of these disorders require the use of suitable model systems that accurately reproduce the human situation. In this article we focus on the possibilities of using the human NT-2 teratocarcinoma cell line for studies on neuronal differentiation, cellular function and neurodegeneration. Neurons generated from undifferentiated NT-2 precursor cells show neuronal morphology, express neuronal markers, exhibit action potentials and have the advantage of homogeneous cellular composition of clonally derived cells. They release a number of different neurotransmitters, respond to stimulation with glutamate, gamma-amino-butyric acid, and nitric oxide, and form functional synapses in culture. Depending on the differentiation protocol, NT-2 cells also have the capacity to develop into glial cells. Different neuronal differentiation procedures and biological properties of NT-2 neurons are described in the text. In transplantation experiments, differentiated NT-2 neurons integrated successfully into the nervous systems of both experimental animals and human patients without evidence for tumor formation, underlining their value for both basic research and clinical applications. We discuss some potential applications in the fields of basic research, drug discovery, and therapy of CNS damage with particular emphasis on neuronal transplantation and different cell death mechanisms in neuronal degeneration. Grafting of NT-2 neurons has been shown to effectively reverse functional defects in animal disease models. Moreover, an ongoing phase 2 randomized clinical trial indicates the safety and feasibility of NT-2 neuron transplantation for the treatment of human patients with cerebral stroke.
Curr Mol Med 2007 Sep
PMID:Human model neurons in studies of brain cell damage and neural repair. 1789 91

Crystal structures, at 1.7 A resolution, were solved for complexes between each of two chemically synthesized partially folded analogues of bovine pancreatic trypsin inhibitor (BPTI) with the proteolytically inactive rat trypsin mutant S195A. The BPTI analogue termed [14-38](Abu) retains only the disulfide bond between Cys14 and Cys38, while Cys5, Cys30, Cys51, and Cys55 are replaced by isosteric alpha-amino-n-butyric acid residues. The analogue K26P,A27D[14-38](Abu) contains two further replacements, by statistically favored residues, in the type I beta-turn that has been suggested to be a main site for initiation of BPTI folding. As a control, the structure of the complex between S195A trypsin and wild-type BPTI was also solved. Despite significant differences in the degree of structure detected among these three BPTIs in solution by several biophysical techniques, their tertiary folds once bound to S195A trypsin in a crystalline lattice are essentially superimposable.
J Mol Biol 2008 Jan 18
PMID:Partially folded bovine pancreatic trypsin inhibitor analogues attain fully native structures when co-crystallized with S195A rat trypsin. 1805 43

Gamma-amino butyric acid (GABA), in addition to being a metabolic intermediate and the main inhibitory neurotransmitter in the synaptic cleft, is postulated as a neurohormone, a paracrine signaling molecule, and a trophic factor. It acts through pre- and post-synaptic receptors, named GABA(A) and GABA(C) (ionotropic receptors) and GABA(B) (metabotropic receptor). Here we reviewed the participation of GABA(B) receptors in the regulation of the hypothalamic-pituitary-gonadal axis, using physiological, biochemical, and pharmacological approaches in rats, as well as in GABA(B1) knock-out mice, that lack functional GABA(B) receptors. Our general conclusion indicates that GABA(B )receptors participate in the regulation of pituitary hormone secretion acting both in the central nervous system and directly on the gland. PRL and gonadotropin axes are affected by GABA(B) receptor activation, as demonstrated in the rat and also in the GABA(B1) knock-out mouse. In addition, hypothalamic and pituitary GABA(B) receptor expression is modulated by steroid hormones. GABA participation in the brain control of pituitary secretion through GABA(B) receptors depends on physiological conditions, being age and sex critical factors.These results indicate that patients receiving GABA(B) agonists/antagonists should be monitored for possible endocrine side effects.
Cell Mol Neurobiol 2008 Sep
PMID:GABA(B) receptors in neuroendocrine regulation. 1826 54

Colorectal cancer is one of the most common cancers in developed countries, and its incidence is negatively associated with high dietary fiber intake. Butyrate, a short-chain fatty acid fermentation by-product of fiber induces cell maturation with the promotion of growth arrest, differentiation, and/or apoptosis of cancer cells. The stimulation of cell maturation by butyrate in colonic cancer cells follows a temporal progression from the early phase of growth arrest to the activation of apoptotic cascades. Previously we performed two-dimensional DIGE to identify differentially expressed proteins induced by 24-h butyrate treatment of HCT-116 colorectal cancer cells. Herein we used quantitative proteomics approaches using iTRAQ (isobaric tags for relative and absolute quantitation), a stable isotope labeling methodology that enables multiplexing of four samples, for a temporal study of HCT-116 cells treated with butyrate. In addition, cleavable ICAT, which selectively tags cysteine-containing proteins, was also used, and the results complemented those obtained from the iTRAQ strategy. Selected protein targets were validated by real time PCR and Western blotting. A model is proposed to illustrate our findings from this temporal analysis of the butyrate-responsive proteome that uncovered several integrated cellular processes and pathways involved in growth arrest, apoptosis, and metastasis. These signature clusters of butyrate-regulated pathways are potential targets for novel chemopreventive and therapeutic drugs for treatment of colorectal cancer.
Mol Cell Proteomics 2008 Jun
PMID:Quantitative and temporal proteome analysis of butyrate-treated colorectal cancer cells. 1834 32

The role of chemical neurotransmission in nematocyst discharge was investigated by stimulating the cnidocils of nematocysts in ablated tentacles of Hydra vulgaris with a piezoelectrically-driven glass probe, in the presence of selected neurotransmitters. Acetylcholine, dopamine, epinephrine, glycine, and serotonin (10(-4), 10(-6), 10(-8) M) per se, did not alter stenotele and desmoneme discharge. gamma-Amino-butyric acid (GABA) significantly increased desmoneme discharge when the cnidocil of another desmoneme in the same or adjacent battery cell complex was stimulated without affecting the discharge rates of the directly stimulated desmonemes or stenoteles. Baclofen (GABA(B) agonist) mimicked the increase; its antagonist, phaclofen, counteracted it. GABA(A) agonists and antagonists did not alter discharge rates. Glutamate caused a dose-dependent increase in the discharge rate of directly stimulated stenoteles; distant stenotele and desmoneme discharge rates were unaffected. Kainate, AMPA, and NMDA, per se, did not alter discharge rates. Co-administration of NMDA and kainate mimicked glutamate's effects. AMPA plus NMDA increased discharge rates. DAP-5 (NMDA antagonist) and CNQX, (kainate/AMPA antagonist) counteracted the increase. The findings suggest that metabotropic GABA is involved in recruiting desmonemes by disinhibiting those previously inhibited, and that the NMDA/kainate-AMPA mechanism regulating Ca(++) entry in higher neuroeffector systems is an early-evolved process, which, in hydra, modulates nematocyst discharge.
Comp Biochem Physiol A Mol Integr Physiol 2008 Aug
PMID:NMDA and GABA B receptors are involved in controlling nematocyst discharge in hydra. 1852 56

Annexin A1 is a member of a phospholipid and calcium binding family of proteins; it is involved in anti-inflammation and in the regulation of differentiation, proliferation, and apoptosis. Here, we show the existence of a functional binding site for the tumor suppressor p53 near the proximal CCAAT box and the fact that the basal expression of annexin A1 in human colon adenocarcinoma cells is driven by p53 at the transcriptional level. Posttranscriptional mechanisms may also play an important role in maintaining constitutive annexin A1 expression. In addition, a p53/NF-Y complex is detected bound to the p53 binding site on its promoter. Butyrate is a natural product of fiber degradation in the colon and a key regulator of colonic epithelium homeostasis. We show that butyrate, a class I and II histone deacetylase inhibitor, induces transcriptional activation of annexin A1 expression correlated with differentiation. The effect of butyrate is mediated through a release of NF-Y from the proximal CCAAT box and an enhancement of p53 binding. The interaction of p53 with the promoter is dependent on p38 MAPK activity either in the absence or in the presence of butyrate. Further, activation of p38 MAPK by this agent is required to increase annexin A1 promoter activity and to increase protein expression.
Mol Cell Biol 2008 Aug
PMID:Upregulation of annexin A1 expression by butyrate in human colon adenocarcinoma cells: role of p53, NF-Y, and p38 mitogen-activated protein kinase. 1854 73

In order to study the human intestinal transit and metabolism of D-galacturonic acid and amidated pectin a number of model experiments were carried out. Both substrates were incubated under aerobic conditions at 37 degrees C using saliva (2 min) and simulated gastric juice (4 h). Under anaerobic conditions the substrates were incubated at 37 degrees C using human ileostomy and colostomy fluids, each obtained from three different donors, for 10 and for 24 h, respectively. D-Galacturonic acid, SCFA (acetic acid, propionic acid, and butyric acid), as well as methanol were analyzed photometrically after carbazole reaction, GC-flame ionization detection (GC-FID), and headspace solid-phase microextraction GC/MS (HS-SPME-GC/MS), respectively. D-Galacturonic acid and amidated pectin were found to be stable during incubations with saliva and simulated gastric juice, whereas both substrates underwent degradation in the course of human ileostomy and colostomy fluid incubations. D-Galacturonic acid was practically completely decomposed within 10 h and SCFA, with acetic acid as the major representative, were formed up to 98% of the incubated substrate in colostomy effluent. The amidated pectin was only degraded in part, revealing stable amounts of 22-35% and 3-17% in ileostomy (after 10 h) and colostomy fluid (after 24 h), respectively. SCFA were generated up to 59% of the applied amidated pectin. In parallel, 19-60% and 52-67% of the available methyl ester groups were cleaved in the course of incubations with ileostomy and colostomy fluids, respectively. The results demonstrate for the first time that D-galacturonic acid and amidated pectin are stable in human saliva and simulated gastric juice. The degradation of both compounds during incubation with ileostomy effluent is highlighted, providing evidence for a considerable metabolic potential of the small intestine.
Mol Nutr Food Res 2008 Jul
PMID:Model experiments mimicking the human intestinal transit and metabolism of D-galacturonic acid and amidated pectin. 1861 79

COMATOSE (CTS), the Arabidopsis homologue of human Adrenoleukodystrophy protein (ALDP), is required for import of substrates for peroxisomal beta-oxidation. A new allelic series and a homology model based on the bacterial ABC transporter, Sav1866, provide novel insights into structure-function relations of ABC subfamily D proteins. In contrast to ALDP, where the majority of mutations result in protein absence from the peroxisomal membrane, all CTS mutants produced stable protein. Mutation of conserved residues in the Walker A and B motifs in CTS nucleotide-binding domain (NBD) 1 resulted in a null phenotype but had little effect in NBD2, indicating that the NBDs are functionally distinct in vivo. Two alleles containing mutations in NBD1 outside the Walker motifs (E617K and C631Y) exhibited resistance to auxin precursors 2,4-dichlorophenoxybutyric acid (2,4-DB) and indole butyric acid (IBA) but were wild type in all other tests. The homology model predicted that the transmission interfaces are domain-swapped in CTS, and the differential effects of mutations in the conserved "EAA motif" of coupling helix 2 supported this prediction, consistent with distinct roles for each NBD. Our findings demonstrate that CTS functions can be separated by mutagenesis and the structural model provides a framework for interpretation of phenotypic data.
Mol Biol Cell 2009 Jan
PMID:Mutations in the Arabidopsis peroxisomal ABC transporter COMATOSE allow differentiation between multiple functions in planta: insights from an allelic series. 1901 87

BCL11A on chromosome 2p16 was recently shown to be a major quantitative trait locus for Hb F level and F-cell number in several populations with or without beta-hemoglobinopathy. We now show that BCL11A isoforms are expressed in K562 cells. Butyrate induction of HBG globin production in K562 is associated with reduced BCL11A. Conversely, augmented expression of BCL11A in K562 cells through transfection of BCL11A expression vector results in more than 50% reduction of HBG promoter transcription activity. This transcription repression can be abrogated by sodium butyrate. BCL11A binds to GGCCGG motif in nucleotide -56 to -51 on the HBG proximal promoter. Together, these data are consistent with BCL11A being able to bind to a core motif in the HBG proximal promoter, recruit and interact with partners to form a repression complex, leading to deacetylation of histones and down-regulation of the HBG transcription.
Blood Cells Mol Dis
PMID:BCL11A represses HBG transcription in K562 cells. 1915 51

The FT-IR and FT-Raman studies have been performed on commercial 3-hydroxy-butyric acid, commercial poly-3-hydroxy butyric acid as well as poly-3-hydroxy butyric acid (PHB) produced by bacteria. The data were compared to those obtained for poly-3-hydroxy butyric acid extracted from natural and genetically modified flax. Genetically modified flax was generated by expression of three bacterial genes coding for synthesis of poly-3-hydroxy butyric acid. Thus transgenic flaxes were enhanced with different amount of the PHB. The discussion of polymer structure and vibrational properties has been done in order to get insight into differences among these materials. The interaction between the cellulose of flax fibers and embedded poly-3-hydroxybutyric acid has been also discussed. The spectroscopic data provide evidences for structural changes in cellulose and in PHB when synthesized in fibers. Based on this data it is suggesting that cellulose and PHB interact by hydrogen and ester bonds.
Spectrochim Acta A Mol Biomol Spectrosc 2009 Jul 15
PMID:Poly-3-hydroxy butyric acid interaction with the transgenic flax fibers: FT-IR and Raman spectra of the composite extracted from a GM flax. 1932 37


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>