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81.
Enzymatic characterization of the pancreatic islet-specific glucose-6-phosphatase-related protein (IGRP) 总被引:5,自引:0,他引:5
Petrolonis AJ Yang Q Tummino PJ Fish SM Prack AE Jain S Parsons TF Li P Dales NA Ge L Langston SP Schuller AG An WF Tartaglia LA Chen H Hong SB 《The Journal of biological chemistry》2004,279(14):13976-13983
Glucose is the main physiological stimulus for insulin biosynthesis and secretion by pancreatic beta-cells. Glucose-6-phosphatase (G-6-Pase) catalyzes the dephosphorylation of glucose-6-phosphate to glucose, an opposite process to glucose utilization. G-6-Pase activity in pancreatic islets could therefore be an important factor in the control of glucose metabolism and, consequently, of glucose-dependent insulin secretion. While G-6-Pase activity has been shown to be present in pancreatic islets, the gene responsible for this activity has not been conclusively identified. A homolog of liver glucose-6-phosphatase (LG-6-Pase) specifically expressed in islets was described earlier; however, the authors could not demonstrate enzymatic activity for this protein. Here we present evidence that the previously identified islet-specific glucose-6-phosphatase-related protein (IGRP) is indeed the major islet glucose-6-phosphatase. IGRP overexpressed in insect cells possesses enzymatic activity comparable to the previously described G-6-Pase activity in islets. The K(m) and V(max) values determined using glucose-6-phosphate as the substrate were 0.45 mm and 32 nmol/mg/min by malachite green assay, and 0.29 mm and 77 nmol/mg/min by glucose oxidase/peroxidase coupling assay, respectively. High-throughput screening of a small molecule library led to the identification of an active compound that specifically inhibits IGRP enzymatic activity. Interestingly, this inhibitor did not affect LG-6-Pase activity, while conversely LG-6-Pase inhibitors did not affect IGRP activity. These data demonstrate that IGRP is likely the authentic islet-specific glucose-6-phosphatase catalytic subunit, and selective inhibitors to this molecule can be obtained. IGRP inhibitors may be an attractive new approach for the treatment of insulin secretion defects in type 2 diabetes. 相似文献
82.
Marco Tartaglia Sonia Valeri Francesco Velardi Concezio Di Rocco P. A. Battaglia 《Human genetics》1997,99(5):602-606
Pfeiffer syndrome is a skeletal disorder characterized by craniosynostosis associated with foot and hand anomalies. Mutations
in the genes encoding fibroblast growth factor receptors 1 and 2 (FGFR1 and FGFR2) have recently been implicated in the aetiology
of such a syndrome, as well as of other craniosynostotic conditions. We now report a novel missense mutation, a G to C transversion
at position 1049 (exon IIIa) of FGFR2, detected in a patient with severe Pfeiffer clinical features. The mutation results
in the substitution of a cysteine for tryptophan-290 in the third immunoglobulin-like domain and affects both spliceoforms
of FGFR2. Mutations causing replacement of tryptophan-290 have also been reported previously in Crouzon syndrome, a similar
but clinically distinct craniosynostotic disorder. This finding confirms the involvement of mutations of FGFR2 exon IIIa in
Pfeiffer syndrome, and emphasizes both the extensive heterogeneity of the FGFR2 mutations that result in the Pfeiffer phenotype
and the perturbations caused by unpaired cysteine residues in receptor dimerization and transduction of the FGFs signal.
Received: 15 August 1996 / Revised: 19 October 1996 相似文献
83.
Canine distemper virus (CDV) infection of ferrets as a model for testing Morbillivirus vaccine strategies: NYVAC- and ALVAC-based CDV recombinants protect against symptomatic infection. 总被引:3,自引:0,他引:3
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C B Stephensen J Welter S R Thaker J Taylor J Tartaglia E Paoletti 《Journal of virology》1997,71(2):1506-1513
84.
Preclinical gastrointestinal prokinetic efficacy and endocrine effects of the ghrelin mimetic RM-131
Lex Van der Ploeg Haley Laken Shubh Sharma Rakesh Datta Heather Halem Jesse Dong Caroline Touvay Marc Teillot Patrick Noonan Lou Tartaglia Liz Stoner Bart Henderson Keith Gottesdiener Michael Culler 《Life sciences》2014
Aims
The 28 amino acid hormone ghrelin, the natural ligand for the growth hormone secretagogue, or ghrelin receptor (GHR), has diverse physiological functions, including a possible role as a gastrointestinal prokinetic. The synthetic ghrelin mimetic RM-131 is in Phase II clinical trials for treatment of diabetic gastroparesis and other gastrointestinal (GI) disorders. We aimed to determine the relative potency of RM-131, when compared to other GI ghrelin mimetics, to predict efficacy and determine the role of RM-131 in models of inflammatory bowel disease.Main methods
We evaluated and compared ghrelin, RM-131 and other synthetic ghrelin mimetics for their prokinetic potency in models of gastrointestinal disorders in the rat and we evaluated the endocrine (rats and dogs) and anti-inflammatory effects (mice) of the ghrelin mimetic RM-131.Key findings
The pentapeptide RM-131 increased gastric emptying in rodent models of ileus. RM-131 is about 100-fold more potent than human ghrelin and is 600 to 1800-fold more potent, when compared to several investigational ghrelin mimetics tested in clinical trials. RM-131 has anti-inflammatory effects and significantly increases survival and reduces macroscopic markers of tissue damage in a TNBS model of inflammatory bowel disease. RM-131 treatment shows a transient increase in growth hormone levels in Beagle dogs and rats, returning to baseline upon chronic treatment. Significant effects on glucose and insulin are not observed in chronic studies.Significance
RM-131's potency, efficacy and endocrine profile, are promising attributes for the treatment of diverse functional gastrointestinal disorders in humans. 相似文献85.
86.
Davide Cirillo Domenica Marchese Federico Agostini Carmen Maria Livi Teresa Botta-Orfila Gian Gaetano Tartaglia 《Genome biology》2014,15(1):R13
Background
RNA-binding proteins regulate a number of cellular processes, including synthesis, folding, translocation, assembly and clearance of RNAs. Recent studies have reported that an unexpectedly large number of proteins are able to interact with RNA, but the partners of many RNA-binding proteins are still uncharacterized.Results
We combined prediction of ribonucleoprotein interactions, based on catRAPID calculations, with analysis of protein and RNA expression profiles from human tissues. We found strong interaction propensities for both positively and negatively correlated expression patterns. Our integration of in silico and ex vivo data unraveled two major types of protein–RNA interactions, with positively correlated patterns related to cell cycle control and negatively correlated patterns related to survival, growth and differentiation. To facilitate the investigation of protein–RNA interactions and expression networks, we developed the catRAPID express web server.Conclusions
Our analysis sheds light on the role of RNA-binding proteins in regulating proliferation and differentiation processes, and we provide a data exploration tool to aid future experimental studies. 相似文献87.
Priya Chatterji Patrick A Williams Kelly A Whelan Fernando C Samper Sarah F Andres Lauren A Simon Louis R Parham Rei Mizuno Emma T Lundsmith David SM Lee Shun Liang HR
Sagara Wijeratne Stefanie Marti Lillian Chau Veronique Giroux Benjamin J Wilkins Gary D Wu Premal Shah Gian G Tartaglia Kathryn E Hamilton 《EMBO reports》2021,22(8)
Correction to: EMBO Reports (2019) 20: e47074. DOI 10.15252/embr.201847074 | Published online 6 May 2019The authors noticed that the control and disease labels had been inverted in their data analysis resulting in publication of incorrect data in Figure 1C. The corrected figure is displayed below. This change affects the conclusions as detailed below. The authors apologize for this error and any confusion it may have caused.In the legend of 1C, change from, “Differential gene expression analysis of pediatric ileal CD patient samples (n = 180) shows increased (> 4‐fold) IMP1 expression as compared to non‐inflammatory bowel disease (IBD) pediatric samples (n = 43)”.Open in a separate windowFigure 1CCorrected Open in a separate windowFigure 1COriginal To, "Differential gene expression analysis of pediatric ileal CD patient samples (n = 180) shows decreased (> 4‐fold) IMP1 expression as compared to non‐inflammatory bowel disease (IBD) pediatric samples (n = 43)”.In abstract, change from, “Here, we report increased IMP1 expression in patients with Crohn''s disease and ulcerative colitis”.To, “Here, we report increased IMP1 expression in adult patients with Crohn''s disease and ulcerative colitis”.In results, change from, “Consistent with these findings, analysis of published the Pediatric RISK Stratification Study (RISK) cohort of RNA‐sequencing data 38 from pediatric patients with Crohn''s disease (CD) patients revealed that IMP1 is upregulated significantly compared to control patients and that this effect is specific to IMP1 (i.e., other distinct isoforms, IMP2 and IMP3, are not changed; Fig 1C)”.To, “Contrary to our findings in colon tissue from adults, analysis of published RNA‐sequencing data from the Pediatric RISK Stratification Study (RISK) cohort of ileal tissue from children with Crohn’s disease (CD) 38 revealed that IMP1 is downregulated significantly compared to control patients in the RISK cohort and that this effect is specific to IMP1 (i.e., other distinct isoforms, IMP2 and IMP3, are not changed; Fig 1C)”.In discussion, change from, “Indeed, we report that IMP1 is upregulated in patients with Crohn''s disease and ulcerative colitis and that mice with Imp1 loss exhibit enhanced repair following DSS‐mediated damage”.To “Indeed, we report that IMP1 is upregulated in adult patients with Crohn''s disease and ulcerative colitis and that mice with Imp1 loss exhibit enhanced repair following DSS‐mediated damage”. 相似文献
88.
Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype
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Carta C Pantaleoni F Bocchinfuso G Stella L Vasta I Sarkozy A Digilio C Palleschi A Pizzuti A Grammatico P Zampino G Dallapiccola B Gelb BD Tartaglia M 《American journal of human genetics》2006,79(1):129-135
Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart disease, and multiple skeletal and hematologic defects. NS is an autosomal dominant trait and is genetically heterogeneous. Gain of function of SHP-2, a protein tyrosine phosphatase that positively modulates RAS signaling, is observed in nearly 50% of affected individuals. Here, we report the identification of heterozygous KRAS gene mutations in two subjects exhibiting a severe NS phenotype with features overlapping those of cardiofaciocutaneous and Costello syndromes. Both mutations were de novo and affected exon 6, which encodes the C-terminal portion of KRAS isoform B but does not contribute to KRAS isoform A. Structural analysis indicated that both substitutions (Val152Gly and Asp153Val) perturb the conformation of the guanine ring-binding pocket of the protein, predicting an increase in the guanine diphosphate/guanine triphosphate (GTP) dissociation rate that would favor GTP binding to the KRASB isoform and bypass the requirement for a guanine nucleotide exchange factor. 相似文献
89.
Calamai M Tartaglia GG Vendruscolo M Chiti F Dobson CM 《Journal of molecular biology》2009,387(4):965-7083
We have performed an extensive mutational analysis of aggregation and disaggregation of amyloid-like protofibrils of human muscle acylphosphatase. Our findings indicate that the regions that promote aggregation in 25% (v/v) 2,2,2 trifluoroethanol (TFE) are different from those that promote disaggregation under milder conditions (5% TFE). Significant changes in the rate of disaggregation of protofibrils in 5% TFE result not only from mutations situated in the regions of the sequence that play a key role in the mechanism of aggregation in 25% TFE, but also from mutations located in other regions. In order to rationalise these results, we have used a modified version of the Zyggregator aggregation propensity prediction algorithm to take into account structural rearrangements of the protofibrils that may be induced by changes in solution conditions. Our results suggest that a wider range of residues contributes to the stability of the aggregates in addition to those that play an important kinetic role in the aggregation process. The mutational approach described here is capable of providing residue-specific information on the structure and dynamics of amyloid protofibrils under conditions close to physiological and should be widely applicable to other systems. 相似文献
90.
Martinelli S Nardozza AP Delle Vigne S Sabetta G Torreri P Bocchinfuso G Flex E Venanzi S Palleschi A Gelb BD Cesareni G Stella L Castagnoli L Tartaglia M 《The Journal of biological chemistry》2012,287(32):27066-27077
Activating mutations in PTPN11 cause Noonan syndrome, the most common nonchromosomal disorder affecting development and growth. PTPN11 encodes SHP2, an Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase that positively modulates RAS function. Here, we characterized functionally all possible amino acid substitutions arising from single-base changes affecting codons 62 and 63 to explore the molecular mechanisms lying behind the largely invariant occurrence of the Y62D and Y63C substitutions recurring in Noonan syndrome. We provide structural and biochemical data indicating that the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase (PTP) domains is perturbed in both mutants as a result of an extensive structural rearrangement of the N-SH2 domain. Most mutations affecting Tyr(63) exerted an unpredicted disrupting effect on the structure of the N-SH2 phosphopeptide-binding cleft mediating the interaction of SHP2 with signaling partners. Among all the amino acid changes affecting that codon, the disease-causing mutation was the only substitution that perturbed the stability of the inactive conformation of SHP2 without severely impairing proper phosphopeptide binding of N-SH2. On the other hand, the disruptive effect of the Y62D change on the autoinhibited conformation of the protein was balanced, in part, by less efficient binding properties of the mutant. Overall, our data demonstrate that the selection-by-function mechanism acting as driving force for PTPN11 mutations affecting codons 62 and 63 implies balancing of counteracting effects operating on the allosteric control of the function of SHP2. 相似文献