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)

We have presently investigated the putative protective role of hemin against the inhibitory actions of the cytokine interleukin-1 beta (IL-1 beta) on isolated rat pancreatic islets. For this purpose, islets were isolated from adult rats, pre-cultured for 3-7 days in RPMI 1640 medium + 10% fetal calf serum and then exposed to IL-1 beta (5 ng/ml), hemin for 1, 7 or 24 h after which islet nitrite production, aconitase activity, glucose oxidation rates, glucose-stimulated insulin release and medium insulin accumulation were determined. It was found that hemin did not prevent IL-1 beta induced nitrite production. On the other hand, hemin partially counteracted the IL-1 beta induced decrease in aconitase activity, glucose oxidation, insulin release and medium insulin accumulation. This protective effect was present at a hemin concentration of 10 microM and most pronounced at 100 microM. Furthermore, hemin induced the synthesis of a 31 kDa protein, which was shown to be heme oxygenase as demonstrated by Western blot analysis. Finally, the protease inhibitor N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK), which protects against IL-1 beta by decreasing nitric oxide production, was found to act additively in combination with hemin in alleviating the IL-1 beta effects. It is proposed that the beneficial effects of hemin against IL-1 beta could be related to scavenging of nitric oxide and/or an increased resistance to nitric oxide production.
Mol Cell Endocrinol 1994 Jul
PMID:Protective action by hemin against interleukin-1 beta induced inhibition of rat pancreatic islet function. 795 87

Uterine expression of the mRNA encoding antileukoproteinase (ALP) is highest in pig uterus during mid- to late pregnancy, suggesting a stage of pregnancy-dependent role for this elastase/cathepsin G protease inhibitor in feto-maternal interactions. To examine a potential relationship between uterine synthesis of ALP and the type of placentation in mammalian species, the expression of ALP mRNA and/or protein in pregnant mares, cows, rats, and mice was evaluated. Genomic DNA and mRNA hybridization analyses were performed using a porcine ALP cDNA as probe. The concentration of ALP protein in reproductive tissues was determined by RIA using a polyclonal antibody raised against a synthetic peptide (ALP 16P) corresponding to amino acid residues 21-36 of the porcine ALP protein. A single ALP mRNA transcript of approximately 0.8 kb in length was detected in equine and bovine uterine tissues. The relative abundance of ALP mRNA in equine endometrium increased between days 125-170 (mid-pregnancy), and then decreased by day 215 of pregnancy. Similarly, the steady state levels of ALP mRNA in bovine endometrium and myometrium were higher during mid- to late than during early pregnancy. The levels of ALP mRNA in bovine fetal cotyledon were low and did not change significantly with stage of pregnancy. No hybridization was detected to pregnant rat endometrial tissues, although high stringency Southern blot analysis of porcine, bovine, and rat genomic DNAs using porcine ALP cDNA as probe predicted a high degree of nucleotide sequence homology in their respective ALP genes.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Reprod Dev 1994 Aug
PMID:Pregnancy-associated endometrial expression of antileukoproteinase gene is correlated with epitheliochorial placentation. 798 Sep 43

Nuclear factor kappa B (NF-kappa B) is a ubiquitous transcription factor which binds to decameric DNA sequences (kappa B sites) and regulates transcription of multiple genes. The activity of NF-kappa B is regulated by an inhibitor protein, I kappa B, which sequesters NF-kappa B in the cytoplasm. Release of I kappa B and subsequent nuclear translocation of NF-kappa B generally require activating signals. However, in mature murine B cells, the DNA-binding activity of NF-kappa B is constitutively nuclear and activates the Ig kappa gene, a marker for mature B cells. To understand the basis for the constitutive NF-kappa B activation, we examined the properties of NF-kappa B and I kappa B in both pre-B and mature B cells, the regulated and constitutive states, respectively. We found that expression of I kappa B alpha and p105, members of the I kappa B family, and Rel, a member of the NF-kappa B family, is augmented in mature B cells. Both I kappa B alpha and p 105 are associated with NF-kappa B proteins and sequester most of these proteins in the cytoplasm of mature B cells. However, rapid I kappa B alpha dissociation and degradation lead to continuous nuclear translocation of a small fraction of NF-kappa B proteins, which represent the constitutively active NF-kappa B in mature B cells. We estimate that the protease activity is at least 35-fold greater in mature B cells than in pre-B cells. Rapid degradation of I kappa B alpha is directly involved in constitutive NF-kappa B activation, because stabilization of I kappa B alpha by a protease inhibitor causes loss of NF-kappa B activity in mature B cells. These results provide evidence that continuous and rapid degradation of I kappa B alpha in the absence pf external stimuli is causally involved in the constitutive activation of NF-kappa B in mature murine B cells.
Mol Cell Biol 1994 May
PMID:Enhanced I kappa B alpha degradation is responsible for constitutive NF-kappa B activity in mature murine B-cell lines. 816 80

The crystal structure of Bowman-Birk type protease inhibitor A-II from peanut was refined at 2.3 A resolution using a restrained least-squares method. The crystallographic R-factor is 0.196 for 7697 reflections with F > 3 sigma (F) in the range from 6.0 to 2.3 A resolution. Two molecules in an asymmetric unit are independently refined and, their structures are compared with each other. The inhibitor molecule has an elongated shape with two reactive sites, one at both ends of the longest dimension. As a secondary structure, a 4-stranded beta-sheet-like structure is found, in which two water molecules bind two 2-stranded beta-sheets together with six hydrogen bonds. The molecule is constructed by two homologous domains which are related by an intramolecular pseudo 2-fold axis. The structure and atomic B-factors of peptide loops containing a reactive site were compared with that of adzuki bean Bowman-Birk type inhibitor in the complex with bovine beta-trypsin. This comparison shows that no significant structural change occurs in the reactive site of inhibitor at the formation of the inhibitor-protease complex, but structural rigidity around the reactive site seems to increase.
J Mol Biol 1993 Dec 05
PMID:Crystallographic refinement of Bowman-Birk type protease inhibitor A-II from peanut (Arachis hypogaea) at 2.3 A resolution. 825 69

The effects of thiol protease inhibitors on fodrin (a cell membrane nonerythroid spectrum-like protein) degradation were studied during hypoxia in cultured myocytes. Cardiac myocytes, isolated from neonatal rat hearts, were incubated under hypoxic conditions for 6 h. Cell membrane proteins, including fodrin, prepared from hypoxic myocytes were examined with electroblots stained for fodrin by the peroxidase method. Cell death during hypoxia rose to 80% after 6 h. Intracellular protease activity was also elevated in hypoxia. This intracellular protease activity was markedly inhibited by the cysteine protease inhibitor E-64 and calpain inhibitor 1. Hypoxic cell death was also suppressed by E-64 and calpain inhibitor 1. A 125 kDa immunoreactive degradation product of fodrin was found in hypoxic conditions. Treatment with E-64 and calpain inhibitor 1 decreased both the appearance of this band and the degradation of fodrin. These observations indicate that intracellular thiol proteases, including calpains, are activated during hypoxia and that these are related to cell membrane protein degradation, especially of fodrin. The data also suggest that protease inhibitor E-64 treatment may be beneficial in protection against hypoxic myocyte injury.
J Mol Cell Cardiol 1993 Sep
PMID:Effects of thiol protease inhibitors on fodrin degradation during hypoxia in cultured myocytes. 828 73

alpha 1-Antitrypsin (alpha 1AT) is a major protease inhibitor present in high concentrations in the plasma. Inheritance of alpha 1AT deficiency or null alleles (alleles associated with no detectable serum alpha 1AT) is associated with an increased risk for emphysema. In contrast to beta zero-thalassemia variants in which RNA splicing and promoter mutations constitute more than 40% of beta zero-thalassemia variants, all nine alpha 1AT null variants identified are the result of mutations involving the protein coding region of the alpha 1AT gene. During routine screening of individuals applying for enrollment in the USA alpha 1AT Deficiency Registry we identified an individual with emphysema and a Protease Inhibitor (PI*) type heterozygous for a novel alpha 1AT null allele. Direct DNA sequencing of this individual's alpha 1AT alleles demonstrated one normal and one novel allele, designated PI*QOwest, characterized by a single G-->T base substitution at position 1 of intron II, a highly conserved nucleotide position in vertebrate splice donor sites. Metabolic labeling of NIH-3T3 cells transfected with a plasmid vector containing an alpha 1AT minigene with the QOwest mutation demonstrated an absence of detectable immunoprecipitable alpha 1AT confirming that the G-->T mutation is responsible for the observed null phenotype. QOwest alpha 1AT minigene transfected cells expressed 25-100 fold less alpha 1AT mRNA than a normal control. DNA sequencing of polymerase chain reaction amplified mRNA obtained from transfected cells demonstrated the use of a cryptic splice site 84 bases upstream from the normal splice site.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1993 Jul
PMID:Characterization of a human alpha 1-antitrypsin null allele involving aberrant mRNA splicing. 836 36

We present the application of free energy perturbation theory/molecular dynamics to predict the consequence of replacing each of the seven peptide bonds in the potent HIV protease inhibitor JG365: ACE (acetyl)-Ser-Leu-Asn-HEA (hydroxyethylamine analog of Phe-Pro)-Ile-Val-NME (N-methyl) by ethylene or fluoroethylene isosteres. Replacing two of these bonds may well lead to significantly tighter binding; replacing two others is predicted to significantly diminish the binding affinity. Also, for three of the peptide bonds fluoroethylene replacements could lead to increased binding of free energies of the inhibitors. Our results should be considered as predictive since there are, as yet, no experimental results on such peptide replacements as enzyme inhibitors.
J Comput Aided Mol Des 1993 Jun
PMID:Peptide mimetics as enzyme inhibitors: use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor. 837 26

Deposits of beta-amyloid are one of the main pathological characteristics of Alzheimer's disease. The beta-amyloid peptide (or beta/A4) constituent of these deposits is derived from the beta-amyloid precursor protein (beta APP), which is expressed in several isoforms. It has been suggested that an imbalance in the normal ratio between the Kunitz protease inhibitor (KPI)-containing beta APPs versus the non containing forms could result in altered processing of beta APP and progressive beta/A4 deposition. We have studied the expression of four beta APP isoforms in the rat brain after intracerebroventricular application of kainic acid. Increased levels of the KPI-containing beta APP and GFAP mRNAs were observed in tissues surrounding areas of neuronal damage. A parallel increase of beta APP and GFAP immunoreactivity was observed in reactive astrocytes in these areas. These results suggest that the normal ratio of beta APP isoforms may be profoundly altered as a result of neuronal damage and that non-neuronal cells may respond to neuronal injury by increased expression of the KPI-containing beta APP isoforms.
Brain Res Mol Brain Res 1993 Jan
PMID:Increased levels of the Kunitz protease inhibitor-containing beta APP mRNAs in rat brain following neurotoxic damage. 838 8

Protein degradation in the exocytic pathway was studied in Saccharomyces cerevisiae using human alpha-1-protease inhibitor (A1Pi) as a reporter molecule. Yeast cells transformed with A1Pi cDNA genes synthesized A1Pi that entered the secretion pathway and accumulated in the endoplasmic reticulum (ER). Cells expressing A1PiM (wild-type) accumulated about 10-fold more A1Pi than cells expressing A1PiZ (secretion defective variant). Analyses of A1Pi mRNA indicated that the low level of A1PiZ relative to A1PiM was not the result of differential gene transcription. Pulse-chase A1Pi radiolabeling showed that A1PiM and A1PiZ were degraded at different rates and suggested a rapid specific turnover of newly synthesized A1PiZ in the ER. Accumulated A1Pi was degraded at comparable rates in both wild-type cells and cells deficient in vacuolar protease activity, indicating that degradation of A1Pi did not occur in the vacuole. Studies to investigate the intracellular location of the degradative process, using temperature-sensitive secretion defective yeast strains, suggested the possibility that degradation occurs not only in the ER but at a second site accessed by vesicle transport. Together, these results demonstrate that a selective protein degradation process operates early in the yeast cell exocytic pathway.
Mol Biol Cell 1993 Jul
PMID:Selective protein degradation in the yeast exocytic pathway. 840 Apr 58

Large crystals of probable amylase/protease inhibitor-B have been grown at room temperature from ammonium sulfate solution. The crystals grow within five days to dimensions of 0.6 mm x 0.6 mm x 0.6 mm. They diffract to at least 1.7 A upon exposure to synchrotron X-rays. The crystals belong to the space group P4(1)2(1)2 (or P4(3)2(1)2) with unit cell dimensions of a = 38.02 A and c = 98.98 A. The presence of one molecule per asymmetric unit gives the unit cell volume per protein mass (Vm) of 1.99 A3/Da and the solvent fraction of 38.2% by volume. X-ray data have been collected to 2.0 A Bragg spacing from native crystals.
J Mol Biol 1993 Jan 05
PMID:Crystallization and preliminary X-ray crystallographic analysis of probable amylase/protease inhibitor-B from rice seeds. 842 10


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