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Query: UNIPROT:P06889 (Mol)
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We have sequenced four new mitochondrial genomes to improve the stability of the tree for placental mammals; they are two insectivores (a gymnure, Echinosorex gymnurus and Formosan shrew Soriculus fumidus); a Formosan lesser horseshoe bat (Rhinolophus monoceros); and the New Zealand fur seal (Arctocephalus forsteri). A revision to the hedgehog sequence (Erinaceus europaeus) is also reported. All five are from the Laurasiatheria grouping of eutherian mammals. On this new data set there is a strong tendency for the hedgehog and its relative, the gymnure, to join with the other Laurasiatherian insectivores (mole and shrews). To quantify the stability of trees from this data we define, based on nuclear sequences, a major four-way split in Laurasiatherians. This ([Xenarthra, Afrotheria], [Laurasiatheria, Supraprimates]) split is also found from mitochondrial genomes using either protein-coding or RNA (rRNA and tRNA) data sets. The high similarity of the mitochondrial and nuclear-derived trees allows a quantitative estimate of the stability of trees from independent data sets, as detected from a triplet Markov analysis. There are significant changes in the mutational processes within placental mammals that are ignored by current tree programs. On the basis of our quantitative results, we expect the evolutionary tree for mammals to be resolved quickly, and this will allow other problems to be solved.
Mol Biol Evol 2002 Dec
PMID:Four new mitochondrial genomes and the increased stability of evolutionary trees of mammals from improved taxon sampling. 1244 98

Otariid lactation and neonatal growth are cyclical processes tied to maternal foraging and nursing patterns (i.e. at sea and on land). Both mother and pup undergo repeated shifts from a positive to a negative energy balance, the physiological mechanisms of which are unclear. We measured plasma and tissue lipoprotein lipase (LPL) in free-ranging northern fur seal mother-pup pairs throughout the first month of lactation. Plasma LPL levels were similar in lactating females (11.3-15.9 U) and growing neonates (8.2-15.2 U). Mammary LPL activity was variable, but highest during the attendance period (3.1 U), while maternal blubber LPL was consistently low (<0.5 U). Neonatal blubber LPL activity was also low (0.2-0.4 U) in accordance with their low growth rates and relatively limited blubber deposition.
Comp Biochem Physiol A Mol Integr Physiol 2003 Jan
PMID:Lipoprotein lipase in lactating and neonatal northern fur seals: exploring physiological management of energetic conflicts. 1250 18

In avian species, a glycoprotein homologous to mammalian ZPC is synthesized in the granulosa cells of developing follicles. We have previously reported that the newly synthesized ZPC (proZPC) in the granulosa cells is cleaved at the consensus furin cleavage site to generate mature ZPC prior to secretion. In the present study, we examined the role of asparagine (N)-linked oligosaccharides in the proteolytic processing of proZPC and the subsequent secretion of ZPC by using site-directed mutagenesis of the consensus sequence for N-glycosylation, and tunicamycin, an inhibitor for N-glycosylation of glycoprotein. Western blot analysis demonstrated that tunicamycin did not block either proteolytic cleavage of proZPC or the subsequent ZPC secretion. Moreover, a site-directed mutant that possesses a mutated sequence for N-glycosylation was efficiently secreted from the cells. These results indicate that proteolytic cleavage of proZPC, and the subsequent ZPC secretion occur in the absence of N-linked oligosaccharides. Therefore, the addition of N-glycans to ZPC polypeptide is not required for quail ZPC secretion.
Comp Biochem Physiol A Mol Integr Physiol 2003 Mar
PMID:Asparagine-linked oligosaccharide-independent secretion of egg envelope glycoprotein ZPC of the Japanese quail (Coturnix japonica). 1260 Jun 72

Corynebacterium diphtheriae DtxR is an iron-specific repressor of diphtheria toxin expression and iron homeostasis functions. A homologue, MntR, serves as a manganese-specific repressor of Mn(II) uptake in Bacillus subtilis. When expressed in B. subtilis, DtxR regulates gene expression in response to either iron or manganese with comparable sensitivity. Replacement of two amino acids in the metal-sensing site with the corresponding residues from MntR results in a DtxR mutant that is highly selective for Mn(II). However, iron responsiveness can be partially restored in a fur mutant in which iron uptake is derepressed and intracellular iron pools elevated. Conversely, if the putative metal-binding residues in MntR are altered to those in DtxR, the resulting protein responds to both iron and manganese. These results suggest that the composition and geometry of the metal-binding site plays a major role in defining the metal-selectivity in this protein family. However, the broadened selectivity of DtxR when expressed in B. subtilis, and the effects of a fur mutation, demonstrate that cellular milieu also influences metal responsiveness.
Mol Microbiol 2003 Apr
PMID:Origins of metal ion selectivity in the DtxR/MntR family of metalloregulators. 1267 7

Glucagon-like peptide-1 (GLP-1) is a potent insulinotrophic hormone, which makes GLP-1 an attractive candidate for the treatment of type 2 diabetes. However, the short plasma half-life of the active forms of GLP-1 poses an obstacle to the sustained delivery of this peptide. In this study, we evaluated the effect of GLP-1 gene delivery both in vitro and in vivo using a new plasmid constructed with a modified GLP-1 (7-37) cDNA. This cDNA contains a furin cleavage site between the start codon and the GLP-1 coding region. The expression of the GLP-1 gene was driven by a chicken beta-actin promoter (pbetaGLP1). The level of the GLP-1 mRNA was evaluated by RT-PCR 24 h after transfection. The in vitro results showed a dose-dependent expression of GLP-1. Coculture assay of the GLP-1 plasmid-transfected cells with isolated rat islet cells demonstrated that GLP-1 increased insulin secretion by twofold, compared to controls during a hyperglycemic challenge. A single injection of polyethyleneimine/pbetaGLP1 complex into ZDF rats resulted in increasing insulin secretion and decreasing blood glucose level that was maintained for 2 weeks. This GLP-1 gene delivery system may provide an effective and safe treatment modality for type 2 diabetes.
Mol Ther 2003 Apr
PMID:GLP-1 gene delivery for the treatment of type 2 diabetes. 1272 10

Long-term constitutive secretion of insulin by implantation of ex vivo transfected cells such as fibroblasts or myoblasts or in situ by intramuscular injection of naked plasmid DNA provides a potential approach to gene therapy for diabetes mellitus. A mechanism for regulating insulin secretion will be necessary to realize the therapeutic potential of this approach. A second obstacle is the inability of non-endocrine host cells to fully process proinsulin. Therefore, alteration of the wild-type cDNA will be necessary to achieve processing of proinsulin by endogenous endoproteases within these cells. The cDNAs for beta-galactosidase (beta), human wild-type proinsulin (hppI1) and a mutated construct (hppI4), in which the dibasic PC2 and PC3 cleavage sites had been altered to form furin cleavage sites, were sub-cloned into four vectors (pCR3, pVR1012, pIRES, pTRE), including a tetracycline responsive plasmid (pTRE) that requires co-transfection with another plasmid encoding a transactivator (pTet-off) for transgene expression. Transient transfection of the COS-7 fibroblast cell line with these constructs was performed using DEAE-dextran and liposomes. Analysis of vector efficiencies revealed that pTRE/pTet-off>pIRES>pCR3>pVR1012. Further analysis demonstrated total pro/insulin secretion of 2.33 ng/10(6) cells/24 h with > or =25% processed to insulin in hppI-1.pTRE/pTet-off-transfected cells compared with 0.39 ng/10(6) cells/24 h and >70% processing in hppI-4.pTRE/pTet-off-transfected cells. In co-transfection studies with pTRE-hppI1/pTet-off and pTRE-hppI4/pTet-off constructs, pro/insulin secretion was inhibited to 65-66% and 36-38% of control (100%) in the presence of 0.01 and 0.1 microg/ml tetracycline respectively over a 24-h incubation period. Furthermore, reversal of tetracycline inhibition was demonstrated for pTRE-hppI1/pTet-off- and pTRE-hppI4/pTet-off-transfected cells. After a 48-h incubation with 1.0 microg/ml tetracycline, total pro/insulin levels were 10 and 14% compared with untreated cells respectively. On tetracycline removal, total proinsulin levels increased and were equivalent to untreated groups 72 h later. In conclusion, regulation of fully processed human insulin secretion has been achieved in a transiently transfected non-endocrine cell line.
J Mol Endocrinol 2003 Jun
PMID:Tetracycline-regulated secretion of human insulin in a transfected non-endocrine cell line. 1279 Aug 3

Proprotein convertases (PC) are a family of serine endoproteases that play important roles in regulating cell function by converting proproteins to biologically active molecules. Several lines of evidence suggest that overexpression of PCs contributes to tumor formation and progression in various types of cancer. In this study, we examined PC expression in six normal ovarian surface epithelium (OSE) cultures, nine primary ovarian cancer (OC) cultures, and three established OC cell lines (Hey, HeyC2, and OCC-1). Our results show that furin and PC7 expression in OC cells was comparable to that in normal OSE. However, PACE4 expression was greatly reduced in all OC samples studied. PACE4 promoter activity was measured in HeyC2 and OCC-1 cells using transiently transfected luciferase reporter plasmids. Both cell lines supported PACE4 promoter activity, showing that the transcription factors critical for PACE4 expression are present in OC cells. The observation that established OC cell lines have reduced PACE4 expression, but maintained the ability to support PACE4 promoter activity, led to the hypothesis that reduced expression may be due to epigenetic modification of the PACE4 gene, such as DNA methylation and histone deacetylation. Methylation analysis of 79 CpG dinucleotides within the PACE4 promoter and exon I (-196/+340) revealed that the percentage of methylated cytosine nucleotides was 8-9% in normal OSE, but 58-93% in OC cells. Treatment with the demethylating agent 5-aza-2'-deoxycytidine and/or the histone deacetylase inhibitor trichostatin A greatly increased PACE4 expression in OC cells. These data suggest that the reduction of PACE4 expression in OC cells is caused, in part, by DNA hypermethylation and histone deacetylation.
Mol Cancer Res 2003 Jun
PMID:Epigenetic regulation of proprotein convertase PACE4 gene expression in human ovarian cancer cells. 1280 4

The Helicobacter pylori genome contains a gene (hp1338 or nikR) that encodes a nickel-dependent regulator that is homologous to the Escherichia coli nickel-responsive regulator, NikR. The H. pylori nikR product acts as a pleiotropic metal-dependent regulator. We constructed a non-polar isogenic mutant deleted for the nikR gene. NikR was essential for the survival of H. pylori in the presence of high nickel and cobalt ion concentrations in vitro. We screened a DNA macroarray for genes that were differentially expressed in parental and nikR-deficient H. pylori strains grown in the presence of excess nickel. We found that H. pylori NikR mediates the expression of nickel-activated and -repressed genes. In the presence of excess nickel, NikR activated the transcription of ureA-ureB (hp72-73), nixA (hp1077 ), copA2 (hp1072), hpn (hp1427 ) and hpn-like (hp1432) genes and repressed the expression of genes encoding proteins involved in ferric iron uptake and storage [pfr (hp0653), fur (hp1027 ), frpB4 (hp1512), exbB/exbD (hp1339-1340), ceuE (hp1561)], motility [cheV (hp616), flaA (hp0601), flaB (hp0115 )], stress responses [hrcA-grpE-dnaK (hp111-110-109)] and encoding outer-membrane proteins [omp11(hp0472), omp31 (hp1469), omp32 (hp1501)]. Slot blot DNA/RNA hybridization experiments using RNA from three independent bacterial cultures confirmed the transcriptome data for 10 selected genes. The results of gel shift experiments using purified native NikR, beta-galactosidase assays with the region between nikR and the exbB/exbD divergent operon, and the study of exbB gene expression using a gentamicin/apramycin reporter gene in H. pylori indicated that NikR is an autorepressor that binds to this intergenic region and also controls the expression of the exbB/exbD/tonB operon, which provides energy for ferric iron uptake. Thus, as previously suggested for Fur in H. pylori, NikR appears to be a global regulator of the metabolism of some divalent cations within a highly complex regulated network.
Mol Microbiol 2003 Aug
PMID:Characterization of the roles of NikR, a nickel-responsive pleiotropic autoregulator of Helicobacter pylori. 1289 20

In teleost fish and tetrapods, the natriuretic peptide (NP) family consists of ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide) and VNP (ventricular natriuretic peptide) that are secreted from the heart, and C-type natriuretic peptide (CNP) that is found in the brain. However, CNP is the only NP identified in the heart and brain of elasmobranchs, suggesting that it is the ancestral type of the NP family and that ANP, BNP and VNP appeared later in the vertebrate phylogeny. To delineate more clearly the molecular evolution of this hormone family, we determined the sequence of NP molecule(s) in evolutionarily the oldest vertebrate group, the cyclostomes. We have cloned a novel NP cDNA from the heart and brain of hagfish, Eptatretus burgeri, using the RACE method and degenerate primers that amplify all known types of NP cDNAs. The novel NP, named EbuNP after the scientific name of this hagfish, appears to be the only NP in the heart and brain, as no other NP cDNAs were amplified even after specific removal of the cloned EbuNP mRNA from the mRNA pool, except for a minor alternatively spliced EbuNP cDNA with a truncated 3'-untranslated sequence. The EbuNP was equally similar to known NPs but was not considered to be a CNP because of the presence of a C-terminal tail sequence. The EbuNP gene was abundantly expressed in the cardiac atrium, ventricle, portal heart and brain but scarcely in the intestine; no expression was observed in the gill and kidney. Mass spectrometry of affinity-purified EbuNP in plasma, heart and brain revealed a 68 amino acid peptide circulating in the blood and stored in the heart, which is cleaved at the typical cleavage signal of a processing enzyme, furin, as observed in mammalian BNP. The C-terminal Gly residue was used for amidation as is the case in eel ANP. The immunoreactive EbuNP was not detected in the brain, suggesting the presence of a different processing form in the brain. These results show that the molecular evolution of the NP family in vertebrates is more complex than previously thought.
J Mol Endocrinol 2003 Aug
PMID:A single and novel natriuretic peptide is expressed in the heart and brain of the most primitive vertebrate, the hagfish (Eptatretus burgeri). 1291 37

SPINK5, encoding the putative multi-domain serine protease inhibitor LEKTI, was recently identified as the defective gene in the severe autosomal recessive ichthyosiform skin condition, Netherton syndrome (NS). Using monoclonal and polyclonal antibodies, we show that LEKTI is a marker of epithelial differentiation, strongly expressed in the granular and uppermost spinous layers of the epidermis, and in differentiated layers of stratified epithelia. LEKTI expression was also demonstrated in normal differentiated human primary keratinocytes (HK) through detection of a 145 kDa full-length protein and a shorter isoform of 125 kDa. Both proteins are N-glycosylated and rapidly processed in a post-endoplasmic reticulum compartment into at least three C-terminal fragments of 42, 65 and 68 kDa, also identified in conditioned media. Processing of the 145 and 125 kDa precursors was prevented in HK by treatment with a furin inhibitor. In addition, in vitro cleavage of the recombinant 145 kDa precursor by furin generated C-terminal fragments of 65 and 68 kDa, further supporting the involvement of furin in LEKTI processing. In contrast, LEKTI precursors and proteolytic fragments were not detected in differentiated HK from NS patients. Defective expression of LEKTI in skin sections was a constant feature in NS patients, whilst an extended reactivity pattern was observed in samples from other keratinizing disorders, demonstrating that loss of LEKTI expression in the epidermis is a diagnostic feature of NS. The identification of novel processed forms of LEKTI provides the basis for future functional and structural studies of fragments with physiological relevance.
Hum Mol Genet 2003 Oct 01
PMID:LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. 1291 42


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