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)

The phylogenetic relationships between the two southern hemisphere lamprey families (Geotriidae and Mordaciidae) and their northern hemisphere counterparts (Petromyzontidae) are unresolved. Insulin was isolated from an extract of islet-containing intestinal tissue from ammocoetes of the Australian lamprey, Mordacia mordax. Its primary structure was established as A-chain: GIVEQCCHRK10CSIYDMENYC20N and B-chain: SALMGTGGTH10LCGSHLVEAL20YVVCGQRGFF30 YTP[SKG]. Although the residues in parentheses are only tentatively assigned, mass spectrometry supports the proposed sequence and demonstrates that Mordacia proinsulin, unlike proinsulin from Geotria australis, is fully processed to mature insulin. Insulins from M. mordax and G. australis and from the northern hemisphere lampreys Petromyzon marinus and Lampetra fluviatilis share a pentapeptide extension to N-terminus of the B-chain (Ser-Ala-Leu-Xaa-Gly) that has never been found in the insulins of any other vertebrate class. This observation provides support for the claim that the Petromyzontiformes constitute a monophyletic group. M. mordax insulin differs from that of G. australis by 18 amino acid residues but by only four residues from the common sequence of P. marinus and L. fluviatilis insulin. These data are consistent with the view that Geotriidae and Mordaciidae have been separated for a long period and suggest that G. australis insulin has undergone an accelerated rate of molecular evolution.
Comp Biochem Physiol B Biochem Mol Biol 2001 May
PMID:The structure of Mordacia mordax insulin supports the monophyly of the Petromyzontiformes and an ancient divergence of Mordaciidae and Geotriidae. 1133 50

Glutamic acid decarboxylase (GAD) 65 is a major autoantigen in type 1 diabetes. Regions of homology exist between GAD65 (residues 250-273) and the Coxsackie P2-C protein (residues 28-50) and between GAD65 (residues 506-518) and proinsulin (residues 24-36), and each of these has been reported to be a diabetes-associated T cell target. The aim of this study was to determine whether the homologous regions are shared targets of T lymphocyte reactivity in individual patients with type 1 diabetes. T cell proliferation against the corresponding peptide pairs, GAD254-276 and Coxsackie P2-C32-54 and GAD506-518 and proinsulin24-36, were measured in peripheral blood mononuclear cells from 26 patients with newly diagnosed type 1 diabetes and 24 control subjects. Responses with stimulation indices higher than 3 were found against each of the antigens tested in both patients and control subjects, and no differences were observed between groups. A strong positive correlation was found between responses to the corresponding peptide pairs GAD254-276 and Coxsackie P2-C32-54 (r=0.77, P<0.0001), and between responses to the corresponding peptide pairs GAD506-518 and proinsulin24-36 (r=0.66, P<0.0001). However, a similar correlation was also observed between responses to the noncorresponding pairs Coxsackie P2-C32-54 and proinsulin24-36 (r=0.82, P<0.0001), Coxsackie P2-C32-54 and GAD506-518 (r=0.82, P<0.0001), and GAD254-276 and proinsulin24-36 (r=0.83, P<0.0001). Strikingly, increased responses to peptides were found almost exclusively in subjects with high stimulation indices against the recall antigen tetanus toxoid, further suggesting that peripheral blood T cell responses are related to a general subject hyperreactivity. These data suggest that proliferative T cell responses to peptides containing putative autoreactive epitopes of GAD65 and proinsulin are not specific for type 1 diabetes, that correlation between T cell reactivity to peptides is not restricted to those containing homologous regions, and that non-antigen-specific factors are important determinants of in vitro measurements of T cell reactivity.
J Mol Med (Berl) 2001 May
PMID:T cell responses to type 1 diabetes related peptides sharing homologous regions. 1140 13

A sandwich-type enzyme-linked immunosorbent assay (ELISA) was established for monitoring the secretion of ZZ-fusion proteins. Two antibodies, a monoclonal mouse anti-human proinsulin and a rabbit anti-bovine IgG (strongly binding to the ZZ-domain), were used to quantify the secretion of recombinant human ZZ-proinsulin to the growth medium of Escherichia coli cultures. The method here reported conjugates the advantages of sandwich-type ELISA assays, namely, high sensitivity, specificity, and throughput, with the possibility of quantifying small protein molecules (e.g., peptides). A further advantage of gene fusion techniques integrating both downstream processing and product detection and quantitation is highlighted. The method is capable of detecting levels of 0.05 ng of ZZ-proinsulin.
Mol Biotechnol 2001 Nov
PMID:A quantitative ELISA for monitoring the secretion of ZZ-fusion proteins using SpA domain as immunodetection reporter system. 1172 20

Type 1 diabetes results from the loss of insulin-producing pancreatic beta cells following the action of beta-cell-specific autoimmune responses. One possible treatment for type 1 diabetes is the development of beta-cell substitutes by introducing an insulin-producing gene into non-beta cells, which would evade the beta-cell-specific autoimmune attack. However, this approach has been hampered by the absence of (1) an appropriate glucose-sensing system to regulate insulin gene transcription; (2) enzymes that process proinsulin to insulin; and (3) glucose-regulatable exocytosis in the target cells. Recent attempts to solve these problems have sought new methods for effective gene transfer and have addressed issues such as the expression and release of insulin in response to the physiological stimulus of glucose, the production of biologically active insulin, and the selection of an ideal target cell for the expression of the insulin gene.
Trends Mol Med 2002 Feb
PMID:Recent advances in insulin gene therapy for type 1 diabetes. 1181 71

For many years, patents and living things have not gotten along well in people's minds; nevertheless, patents are a real right. Even though people accept that a farmer can own a cow or that a Parisian can own a dog, they do not seem to understand that it is possible to patent a recombinant micro-organism or a DNA sequence. This is probably because industrial property is a hybrid concept, which mixes rights and science. Thus, this field is prone to misunderstanding by scientists and jurists, because of its juridical aspects for the former and because of its scientific aspects for the latter. The general public,as a result has two avenues of extravagant questioning to follow and consider. Finally, if industrial property is applied to a living phenomenon, it is often almost impossible to explain in layman's terms the ins and outs of the problems that may arise.
Cell Mol Biol (Noisy-le-grand) 2001 Dec
PMID:Living things, the human genome, and patents. 1183 55

Type 1 diabetes is an organ-specific autoimmune disease whose incidence is increasing worldwide. At present, there is no effective therapy to prevent or cure this disease. The genetic background (MHC and non-MHC genes) and environmental factors (pathogens, drugs, and diet) are critical for the initiation of the autoimmune response against the pancreatic beta-cells. Recognition of the pancreatic autoantigens by T cells in a predetermined environment of antigen-presenting cells, costimulation, and cytokines is crucial for the selective activation of diabetogenic or protective/regulatory T cells. Once the autoimmune process is triggered, epitope spreading and sustaining the autoimmune responses by continuous antigen stimulation leads to expansion of effector cells, which launch the attack on the beta-cells. Despite of some controversy, most of the studies in humans and animal models suggest that CD4 (Th1) T cells are directly involved in the autoimmune attack by secretion of pro-inflammatory cytokines and recruitment of cytotoxic CD8 T cells. Secretion of anti-inflammatory cytokines by Th2 cells is protective against the disease. Therapy with peptides derived from major target antigens, such as glutamic acid decarboxylase 65 or proinsulin, can prevent the disease in animal models by rising protective Th2 cells. Herein, we review the recent progress in the immunopathogenesis of Type 1 diabetes and insights into the development of new diagnostic tools and antigen-specific immunomodulators, such as MHC-peptide chimeras.
Curr Mol Med 2001 Jul
PMID:Insights into the pathogenesis of type 1 diabetes: a hint for novel immunospecific therapies. 1189 83

Vasopressin, oxytocin as well as other active nonapeptides (vasotocin, etc) are difficult to isolate from tissues. Traditionally they were identified using cumbersome biological assays or immunoassays, commercially unavailable, and with some cross reactivity. Based on the fact that all these peptides have two Cysteines in their molecules we developed a simple, sensitive and specific method to detect them by HPLC after pre-column fluorescent derivatization with monobromobimane (mBBr). The peptides were separated on a Vydac C18 column after reduction with Tris (2-carboxyethyl) phosphine (TCEP) and derivatization with mBBr for 5 minutes in dark. Using this method we were able to detect specific peaks for arginine-, lysine-vasopressin, and vasotocin at levels as low as 10 pmol. The method can be used to detect other active peptides with cyst(e)ins in their molecule, as well.
J Cell Mol Med
PMID:A chemical method to isolate hypothalamic nonapeptides by coupling cyst(e)in with bimane. 1206 2

Based on the findings that proinsulin C-peptide binds specifically to cell membranes, we investigated the effects of C-peptide and related molecules on the intracellular Ca2+ concentration ([Ca2+]i) in human renal tubular cells using the indicator fura-2/AM. The results show that human C-peptide and its C-terminal pentapeptide (positions 27-31, EGSLQ), but not the des (27-31) C-peptide or randomly scrambled C-peptide, elicit a transient increase in [Ca2+]i. Rat C-peptide and rat C-terminal pentapeptide also induce a [Ca2+]i response in human tubular cells, while a human pentapeptide analogue with Ala at position 1 gives no [Ca2+]i response, and those with Ala at positions 2-5 induce responses with different amplitudes. These results define a species cross-reactivity for C-peptide and demonstrate the importance of Glu at position 1 of the pentapeptide. Preincubation of cells with pertussis toxin abolishes the effect on [Ca2+]i by both C-peptide and the pentapeptide. These results are compatible with previous data on C-peptide binding to cells and activation of Na-,K+ATPase. Combined, all data show that C-peptide is a bioactive peptide and suggest that it elicits changes in [Ca2+]i via G-protein-coupled pathways, giving downstream enzyme effects.
Cell Mol Life Sci 2002 Jul
PMID:Proinsulin C-peptide and its analogues induce intracellular Ca2+ increases in human renal tubular cells. 1222 64

Although large human populations have been safely immunized against tuberculosis with two live vaccines, Mycobacterium bovis BCG or Mycobacterium microti, the vole bacillus, the molecular basis for the avirulence of these vaccine strains remains unknown. Comparative genomics has identified a series of chromosomal deletions common to both virulent and avirulent species but only a single locus, RD1, that has been deleted from M. bovis BCG and M. microti. Restoration of RD1, by gene knock-in, resulted in a marked change in colonial morphology towards that of virulent tubercle bacilli. Three RD1-encoded proteins were localized in the cell wall, and two of them, the immunodominant T-cell antigens ESAT-6 and CFP-10, were also found in culture supernatants. The BCG::RD1 and M. microti::RD1 knock-ins grew more vigorously than controls in immunodeficient mice, inducing extensive splenomegaly and granuloma formation. Increased persistence and partial reversal of attenuation were observed when immunocompetent mice were infected with the BCG::RD1 knock-in, whereas BCG controls were cleared. Knocking-in five other RD loci did not affect the virulence of BCG. This study describes a genetic lesion that contributes to safety and opens new avenues for vaccine development.
Mol Microbiol 2002 Nov
PMID:Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti. 1241 Aug 28

Prohormones are directed from the trans-Golgi network to secretory granules of the regulated secretory pathway. It has further been proposed that prohormone conversion by endoproteolysis may be necessary for subsequent retention of peptides in granules and to prevent their release by the so-called "constitutive-like" pathway. To address this directly, mutant human proinsulin (Arg/Gly(32):Lys/Thr(64)), which cannot be cleaved by conversion endoproteases, was expressed in primary rat islet cells by recombinant adenovirus. The handling of the mutant proinsulin was compared with that of wild-type human proinsulin. Infected islet cells were pulse labeled and both basal and stimulated secretion of radiolabeled products followed during a chase. Labeled products were quantified by high-performance liquid chromatography. As expected, the mutant proinsulin was not converted at any time. Basal (constitutive and constitutive-like) secretion was higher for the mutant proinsulin than for wild-type proinsulin/insulin, but amounted to <1% even during a prolonged (6-h) period of basal chase. There was no difference in stimulated (regulated) secretion of mutant and wild-type proinsulin/insulin at any time. Thus, in primary islet cells, unprocessed (mutant) proinsulin is sorted to the regulated pathway and then retained in secretory granules as efficiently as fully processed insulin.
Mol Biol Cell 2003 Mar
PMID:Mutant proinsulin that cannot be converted is secreted efficiently from primary rat beta-cells via the regulated pathway. 1263 34


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