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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two [NiFe] hydrogenases enable the proteobacterium Ralstonia eutropha H16 to grow on molecular hydrogen as the sole energy source. A third [NiFe] hydrogenase (RH) acts as an H2 sensor in a multiple component signal transduction chain that controls hydrogenase gene transcription. The RH forms a dimeric heterodimer (HoxBC)2 in which HoxC contains the H2-sensing active site and HoxB the electron-transferring components including an organic, not yet identified redox cofactor. This oligomer forms a tight complex with the histidine protein kinase HoxJ. Both the sensor and the kinase were analysed by mutagenesis for functional domains that are instrumental in H2 signal transmission. A mutant deleted for a C-terminal peptide of 55 amino acids in HoxB lost its H2-sensing ability but still catalysed H2 oxidation. The mutant protein failed to form the dimeric heterodimer and a complex with HoxJ. The organic redox cofactor was no longer detectable in the truncated sensor. H2 sensing was also abolished by deletion of the PAS domain of HoxJ, indicating that this domain is involved in signal transduction. A truncated version of HoxJ consisting of only the input domain of the kinase was still capable of forming a complex with the RH. Mass determination of the purified HoxJ protein revealed that the kinase forms a homotetramer. The unique oligomeric structure of the H2-sensing complex with respect to its regulatory function is discussed.
Mol Microbiol 2004 Mar
PMID:The H2-sensing complex of Ralstonia eutropha: interaction between a regulatory [NiFe] hydrogenase and a histidine protein kinase. 1500 94

Bacterial infections of the lung are known to induce inflammatory responses, which lead to mucus hypersecretion. Moreover, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and its activation. Furthermore, matrix metalloproteinases (MMPs), especially MMP-9, have been reported to promote the transmigration of activated neutrophils. In this study, we investigated the associations between lipopolysaccharide (LPS)-induced goblet cell (GC) metaplasia and EGFR expression and the effects of MMP inhibitor (MMPI). Various concentrations of LPS were instilled into the tracheas of pathogen-free Sprague-Dawley rats, and airways were examined at different times after LPS instillation. To examine the role of MMP-9, we treated rats 3 days before LPS instillation and daily thereafter with MMPI. Neutrophilic infiltration, Alcian blue/periodic acid-Schiff (AB/PAS) staining, and immunohistochemical staining for MUC5AC, EGFR, and MMP-9 were performed. The instillation of LPS increased AB/PAS and MUC5AC staining in time- and dose-dependent manners, and treatment with MMPI significantly prevented GC metaplasia. The instillation of LPS into the trachea also induced neutrophilic infiltration and EGFR and MMP-9 expression in the airway epithelium, and MMPI was found to significantly prevent neutrophil recruitment, GC metaplasia, and EGFR and MMP-9 expression. This study demonstrates that the MMP-9 and EGFR cascades are associated with LPS-induced mucus hypersecretion.
Am J Physiol Lung Cell Mol Physiol 2004 Jul
PMID:Effects of matrix metalloproteinase inhibitor on LPS-induced goblet cell metaplasia. 1502 Feb 97

Endothelial PAS domain protein-1 (EPAS1) regulates transcription of the genes encoding erythropoietin and vascular endothelial growth factor, which are important for maintaining oxygen homeostasis. We have previously shown that plasminogen activator inhibitor-1 (PAI-1) gene expression is induced by hypoxia. In this study, we sought to determine whether PAI-1 gene expression is directly regulated by EPAS1 in cancer cells because activities of proteases and their inhibitors are tightly regulated for tumor invasion. Hypoxia increased the PAI-1 mRNA levels in human adenocarcinoma A549 cells. Overexpression of EPAS1 significantly increased the PAI-1 mRNA and protein levels. Transient transfection assays revealed that EPAS1 increased PAI-1 gene transcription through a sequence containing 5'-CACGTACA-3' located at -194 (we refer to it as site HREPAI-1) and GT-box located at -78. Electrophoretic gel mobility shift assays revealed that HREPAI-1 serves as a binding site for EPAS1, and Sp1 constitutively binds to GT-box. In conclusion, PAI-1 expression is induced by EPAS1 through HREPAI-1 and through an Sp1-binding site. These results indicate that the PAI-1 gene is a direct target of EPAS1 and suggest the role of EPAS1 and Sp1 in the hypoxic response of cancer cells.
Am J Respir Cell Mol Biol 2004 Aug
PMID:The PAI-1 gene as a direct target of endothelial PAS domain protein-1 in adenocarcinoma A549 cells. 1503 36

A growing family of helix-loop-helix PAS (HLH-PAS) transcription factors has emerged recently. These proteins form heterodimers and are involved in adaptation to environmental or physiologic stresses as well as in embryonic development. We describe the cloning and characterization of a novel HLH-PAS protein termed LE-PAS (limbic-enriched PAS) in mouse. LE-PAS consists of 802 amino acids and has a predicted molecular mass of 87.4 kDa. In adult mice, it is expressed exclusively in brain. Northern blot and in situ hybridization analysis indicate that LE-PAS is expressed in the limbic system and olfactory bulb. By in vitro overexpression in COS-7, cells we found that LE-PAS is a nuclear protein. Reporter gene analysis indicated that LE-PAS transactivates the CNS midline enhancer (CME) motif but not the xenobiotic response element in an Arnt-dependent fashion and without prior activation of LE-PAS protein. Our observation suggests that LE-PAS shares a similar mode of function with HLH-PAS proteins such as single minded or trachealess indicating that LE-PAS also has constitutive or developmental functions which may be critical for regulating the transcriptional control of limbic patterning and function.
Brain Res Mol Brain Res 2004 Sep 28
PMID:LE-PAS, a novel Arnt-dependent HLH-PAS protein, is expressed in limbic tissues and transactivates the CNS midline enhancer element. 1536 89

TMEM16A, TMEM16B, TMEM16C, TMEM16D, TMEM16E, TMEM16F and TP53I5 are TMEM16 family eight-transmembrane proteins with N- and C-terminal tails facing the cytoplasm. TMEM16A gene at human chromosome 11q13.3 is amplified in head and neck tumors, and TMEM16E gene at human chromosome 11p14.3 is mutated in gnathodiaphyseal dysplasia (GDD). Ngep cDNA (NM_207031.1) is derived from mouse Tmem16g gene. Here, we characterized human TMEM16G gene by using bioinformatics. TMEM16G gene, consisting of 25 exons, was located at human chromosome 2q37.3. Intra-species comparative genomics revealed that the PASK-PPP1R7-TMEM16G-HDLBP-NEDD5 locus was the unique region without paralogous region. TMEM16G mRNA was preferentially expressed in normal prostate and prostate cancer. Complete coding sequence of TMEM16G cDNA was determined by assembling 25 exons of TMEM16G gene. Human TMEM16G gene was found to encode 932-amino-acid TMEM16G protein with TM16H1, TM16H2 and TM16H3 domains. Comparative proteomics revealed that T844N amino-acid substitution occurred in human TMEM16G during evolution. TMHMM2 program predicted that mouse Tmem16g and artificial human TMEM16G (844T) were eight-transmembrane proteins, but that wild-type human TMEM16G (844N) was a seven-transmembrane protein. These facts indicate that amino-acid substitution at codon 844 of human TMEM16G resulted in the mis-folding of the eighth transmembrane helix. Human TMEM16G with altered membrane topology might show functional divergence compared with other members of the TMEM16 family.
Int J Mol Med 2004 Oct
PMID:Characterization of human TMEM16G gene in silico. 1537 14

First investigations of photoacoustic (PA) spectroscopy (PAS) of methane using an antimonide semiconductor laser are reported. The laser fabrication is made in two steps. The structure is firstly grown by molecular beam epitaxy, then a metallic distributed-feedback (DFB) grating is processed. The laser operates at 2371.6 nm in continuous wave and at room temperature. It demonstrates single-mode emission with typical tuning coefficients of 0.04 nm mA(-1) and 0.2 nm K(-1). PA detection of methane was performed by coupling this laser into a radial PA cell. A detection limit of 20 ppm has been achieved in a preliminary configuration that was not optimised for the laser characteristics.
Spectrochim Acta A Mol Biomol Spectrosc 2004 Dec
PMID:Application of antimonide diode lasers in photoacoustic spectroscopy. 1556 29

Cells have several sensory systems that detect energy and metabolic status and adjust flux through metabolic pathways accordingly. Many of these sensors and signaling pathways are conserved from yeast to mammals. In this review, we bring together information about five different nutrient-sensing pathways (AMP kinase, mTOR, PAS kinase, hexosamine biosynthesis and Sir2), highlighting their similarities, differences and roles in disease.
Comp Biochem Physiol B Biochem Mol Biol 2004 Dec
PMID:Nutrient sensing and metabolic decisions. 1558 87

PERIOD proteins are central components of the Drosophila and mammalian circadian clock. Their function is controlled by daily changes in synthesis, cellular localization, phosphorylation, degradation, as well as specific interactions with other clock components. Here we present the crystal structure of a Drosophila PERIOD (dPER) fragment comprising two tandemly organized PAS (PER-ARNT-SIM) domains (PAS-A and PAS-B) and two additional C-terminal alpha helices (alphaE and alphaF). Our analysis reveals a noncrystallographic dPER dimer mediated by intermolecular interactions of PAS-A with PAS-B and helix alphaF. We show that alphaF is essential for dPER homodimerization and that the PAS-A-alphaF interaction plays a crucial role in dPER clock function, as it is affected by the 29 hr long-period perL mutation.
Mol Cell 2005 Jan 07
PMID:Crystal structure and interactions of the PAS repeat region of the Drosophila clock protein PERIOD. 1562 18

The NifL regulatory protein controls transcription of nitrogen fixation genes in Azotobacter vinelandii by modulating the activity of the transcriptional activator NifA through direct protein-protein interactions. The ability of NifL to integrate the antagonistic signals of redox and nitrogen status is achieved via the involvement of discrete domains in signalling specific environmental cues. NifL senses the redox status via an FAD co-factor located within the amino-terminal PAS domain and responds to the fixed nitrogen status by interaction with the signal transduction protein GlnK, which binds to the C-terminal GHKL domain of NifL. The GHKL domain binds adenosine nucleotides and is similar to the core catalytic domain of the histidine protein kinases. Binding of ADP to this domain increases the inhibitory activity of NifL and the formation of protein complexes with NifA. This inhibition is antagonised by the binding of 2-oxoglutarate, a key metabolic signal of the carbon status, to the amino-terminal GAF domain of NifA. In this study we have examined the properties of three mutations within conserved residues in the GHKL domain of NifL that impair signal transduction. All three mutations decrease the affinity of NifL for ADP significantly, but the mutant proteins exhibit discrete properties. The N419D mutation prevents inhibition of NifA activity by NifL both in vivo and in vitro. In contrast, the G455A and G480A mutations eliminate the redox response, but the mutant proteins retain some sensitivity to the fixed nitrogen status and the ability to interact with the GlnK signal transduction protein. Our data suggest that the absence of the redox switch in the G455A and G480A mutants is a consequence of their inability to override the allosteric effect of 2-oxoglutarate on NifA activity. Overall, these results demonstrate that the binding of adenosine nucleotides to the GHKL domain of NifL plays an important role in counteracting the response of NifA to 2-oxoglutarate, under conditions that are inappropriate for nitrogen fixation.
J Mol Biol 2005 Mar 04
PMID:Mutational analysis of the nucleotide-binding domain of the anti-activator NifL. 1570 8

The PAS (PER-ARNT-SIM) helix-loop-helix transcription factor BMAL1 (also known as MOP3) is an essential component of the circadian pacemaker in mammals. Here we show that the retinoic acid receptor-related orphan receptor RORalpha (NR1F1) directly activates transcription of Bmal1 through two conserved RORalpha response elements that are required for cell-autonomous transcriptional oscillation of Bmal1 mRNA. Positive involvement of RORalpha in generation of the Bmal1 circadian oscillation was verified by behavioral analyses of RORalpha-deficient staggerer mice that showed aberrant locomotor activity and unstable rhythmicity. In cultured cells, loss of endogenous RORalpha protein resulted in a dampened circadian rhythm of Bmal1 transcription, further indicating that RORalpha is a functional component of the cell-autonomous core circadian clock. These results indicate that RORalpha acts to promote Bmal1 transcription, thereby maintaining a robust circadian rhythm.
Nat Struct Mol Biol 2005 May
PMID:The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1. 1582 43


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