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At least 721 records · Page 40Linked to original sources
PubMed2004

Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G>A (p.G93D) variant with reduced functional activity.

Variations of the small heterodimer partner (SHP, NR0B2) gene, an atypical nuclear receptor that inhibits transactivation by hepatocyte nuclear factor (HNF)-4alpha, are associated with obesity among Japanese. The purpose of the study was to evaluate the prevalence of SHP variants among obese Danish men. Using combined SSCP and heteroduplex analysis, we analyzed the entire coding region of SHP for variants in a cohort of 750 Danish men with early-onset obesity and genotyped a cohort of 795 nonobese control subjects using PCR-RFLP. Functional analyses of the identified coding region variants were performed in both MIN6-m9 and HepG2 cell lines. A total of five novel variants, including three missense variants (c.100C>G [p.R34G], c.278G>A [p.G93D], and c.415C>A [p.P139H]) and two silent variants (c.65C>T [p.Y22Y] and c.339G>A [p.P113P]) were identified. Moreover, the previously reported c.512G>C [p.G171A] polymorphism was identified. The 171A allele was not associated with obesity (p = 0.07). The 34G, 93D, and 139H-alleles were rare variants, which were found only among obese subjects. Among the four coding region variants, the 93D-allele showed a reduced in vitro inhibition of the HNF-4alpha transactivation of the HNF-1alpha promoter expression when expressed in MIN6-m9 and HepG2 cell lines (p<0.01). In contrast to reported findings among obese Japanese, functional variants are rare among Danish men. A functional 93D variant of SHP was identified in 1 out of 750 obese and in none of 795 nonobese control subjects. Further large-scale population studies are necessary to assess the clinical impact of this rare variant on obesity risk among European subjects.

Adolescent↗
PubMed1997

Fluid percussion injury causes disruption of the septohippocampal pathway in the rat.

Fluid percussion injury (FPI) causes memory deficits, loss of hippocampal neurons, and basal forebrain cholinergic immunoreactivity in rats. Basal forebrain septohippocampal projections terminate in specific hippocampal regions. The purpose of this study was to examine the effects of FPI on the septohippocampal pathway (SHP). Halothane-anesthetized rats received either a sham injury or a parasagittal FPI. To characterize the anatomical effects of FPI on the SHP, silver stains were performed on brains of animals at 1, 5, and 10 days following FPI and were compared to sham-injured preparations. To characterize the effects of FPI on retrograde transport in the SHP, a separate group of FPI and sham-injured animals with survival times of 2, 5, and 10 days received bilateral WGA-HRP injections into the hippocampal formation 24 h prior to sacrifice. Argyrophilic CA3 neurons were present 1 day following FPI. Five days following FPI, terminal degeneration was present in the inner third of the molecular layer of the dentate gyrus bilaterally that was not present 1 day after injury. Fiber and terminal degeneration was not observed in the basal forebrain until 10 days after FPI. WGA-HRP-labeled septal neurons decreased significantly (P < 0.05) ipsilateral to injury in animals sacrificed 5 and 10 days following FPI but not 2 days after injury. This investigation demonstrated that FPI produces focal injury in the hippocampal formation. In addition, the appearance of terminal degeneration in the dentate molecular layer correlated with the significant reduction in axonal transport 5 days following injury. This correlation illustrates the secondary processes that structurally damage the SHP up to 10 days after injury.

Animals↗
PubMed2000

Identification of natural ligands for SH2 domains from a phage display cDNA library.

The cytoplasmic domain of the Fc gamma receptor IIB (FcgammaRIIB) can be successfully displayed on the surface of filamentous phage, and after phosphorylation in vitro, can interact specifically with the SH2 domains of SHP-2, a cytoplasmic tyrosine phosphatase. When full-length FcgammaRIIB is expressed on phage, however, this interaction is greatly compromised, illustrating that characteristics of the full-length sequence are not well tolerated by the phage display system. Many associations in cell physiology are driven by similar interactions involving small modular binding domains or ligands, and so a fragmented cDNA library will facilitate display of such domains free of sequences which compromise their expression. A fragmented leukocyte cDNA display library of 10(8) clones was constructed. This library was phosphorylated in vitro with fyn kinase and was selected against the tandem SH2 domains of SHP-2 in the search for additional ligands. A depletion strategy to remove non-specific clones was employed, using SHP-2 Sepharose, prior to in vitro phosphorylation and selection. This permitted the emergence of clones encoding the cytoplasmic domain of PECAM-1, another natural ligand for SHP-2. The importance of dual phosphorylation of tyrosine residues at positions 663 and 686 was confirmed in competition ELISA experiments using phosphorylated phage and synthetic peptides. Thus, phage display of fragmented cDNA libraries permits the identification and characterisation of phosphorylated ligands of modular binding domains based on their functional interaction.

Amino Acid Sequence↗
PubMed1998

Regulation of B cell signal transduction by SH2-containing protein-tyrosine phosphatases.

Tyrosyl phosphorylation plays a key role in B lymphocyte signaling. The mechanisms by which protein tyrosine kinases (PTKs) regulate signaling pathways in B cells have been investigated extensively. More recently, attention has turned to the protein--tryosine phosphatases (PTPs), particularly those containing SH2 domains. SHP-1 has been shown to be a critical regulator of antigen receptor signaling, acting, at least in part, via inhibitory co-receptors containing SHP-1 binding sites. These studies have been aided considerably by the analysis of mice carrying naturally-arising mutations in the SHP-1 gene as well as mice bearing targeted mutations in other components of Be cells signaling pathways. The function of SHP-2 in B cells in less clear, although studies in other cell systems suggests that it may play a signal-enhancing role.

Animals↗
PubMed2005

Growth hormone secretion in primary and secondary hyperparathyroidism.

Primary hyperparathyroidism (PHP) is associated with impaired GH secretion. Whether this effect is due to hypercalcemia or to increased serum PTH concentration is unclear. However, patients with familial hypocalciuric hypercalcemia (FHH), who have normal PTH and increased serum calcium concentrations, also have an impaired GH secretion, suggesting that calcium rather than PTH is responsable for this effect on GH secretion. To further investigate this issue, 10 consecutive patients with secondary hyperparathyroidism (SHP) due to vitamin D deficiency were evaluated by the GH response to GHRH+arginine (Arg) test. A group of 60 consecutive untreated PHP patients served as controls. Mean GH response to GHRH+Arg test was 15.8+/-14 microg/l and 37.5+/-16 microg/l (p<0.001) in PHP and in SHP patients, respectively. Forty-two out of 60 (70%) PHP patients had a suppressed or blunted GH response, whereas all SHP patients had normal GH response. The results of the present study confirm and extend our previous observations that PHP is associated with an impaired GH secretion in the majority of cases, and indicate that SHP patients have no abnormality of GH secretion. Thus, hypercalcemia rather than increased serum PTH is responsible for the abnormality of GH secretion.

Adult↗
PubMed2005

Src homology 2-containing phosphotyrosine phosphatase regulates endothelin-1-induced epidermal growth factor receptor transactivation in rat renal tubular cell NRK-52E.

Epidermal growth factor (EGF) and endothelin-1 (ET-1) have been shown to be involved in proliferation and autoregeneration of renal tubular cells. This study aims to investigate the regulatory mechanism of ET-1-mediated EGF receptor (EGFR) transactivation in rat renal tubular cells (NRK-52E). Exposure of NRK-52E cells to ET-1 was found to stimulate the phosphorylation of EGFR and induce reactive oxygen species (ROS) generation. Both NAD(P)H oxidase inhibitor, diphenyliodonium (DPI) and ROS scavenger N-acetylcysteine (NAC), inhibited EGFR transactivation and extracellular signal-regulated kinase (ERK) phosphorylation caused by ET-1. In contrast, blockade of EGFR by AG1478 inhibited the phosphorylation of ERK but not ROS generation following ET-1 exposure. We found that the catalytic cysteine of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) was transiently oxidized by ET-1 treatment in a modified malachite green phosphatase assay. In EGFR co-immunoprecipitation, SHP-2 was also found to interact with EGFR following ET-1 treatment. In SHP-2 knockdown NRK-52E cells, ET-1-induced EGFR transactivation was dramatically elevated and not influenced by NAC. However, GM6001 (an MMP inhibitor) and heparin binding (HB)-EGF neutralizing antibody suppressed this elevation. Our data suggest that ROS-mediated oxidation of SHP-2 is essential for HB-EGF-mediated EGFR transactivation in ET-1 signaling pathway in NRK-52E cells.

Animals↗
PubMed2006

Relationship between the diversity of the cagA gene of Helicobacter pylori and gastric cancer in Okinawa, Japan.

BACKGROUND: Helicobacter pylori CagA protein is considered to be one of the virulence factors associated with gastric cancer. CagA is injected into gastric epithelial cells, undergoes tyrosine phosphorylation, and binds to Src homology 2 domain-containing protein-tyrosine phosphatase (SHP-2). Two major subtypes of CagA have been observed in the SHP-2-binding site, the Western and East Asian types. The East Asian-type CagA binds to SHP-2 more strongly than the Western-type CagA. The diversity of CagA, which collectively determines the binding affinity of CagA to SHP-2, may be an important variable in determining the clinical outcome of infection by different H. pylori strains. METHODS: We investigated the relationship between the diversity of CagA and clinical outcome in Okinawa, Japan. A total 24 strains, 13 gastric cancer strains and 11 duodenal ulcer strains, were studied. We sequenced full-length cagA genes and analyzed the phylogenetic relationships between Okinawa isolates and previously characterized Western H. pylori strains. RESULTS: All isolates examined were cagA positive. The prevalence of East Asian CagA-positive strains was significantly higher in patients with gastric cancer (84.6%) than in patients with duodenal ulcer (27.3%) (chi-squared = 8.06, P = 0.011). The phylogenetic analysis showed that all gastric cancer strains with East Asian-type CagA were in the East Asian cluster, and that most duodenal ulcer strains were in the Western cluster. CONCLUSIONS: The origins of H. pylori isolates are different between gastric cancer strains and duodenal ulcer strains, and East Asian CagA-positive H. pylori infection is associated with gastric cancer. The strain diversity observed in Okinawa may affect the difference in the prevalence of disease associated with H. pylori infection in Japan.

Adult↗
PubMed2005

Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.

Noonan syndrome (NS) is characterized by short stature, characteristic facial features, and heart defects. Recently, missense mutations of PTPN11, the gene encoding protein tyrosine phosphatase (PTP) SHP-2, were identified in patients with NS. Further, somatic mutations in PTPN11 were detected in childhood leukemia. Recent studies showed that the phosphatase activities of five mutations identified in NS and juvenile myelomonocytic leukemia (JMML) were increased. However, the functional properties of the other mutations remain unidentified. In this study, in order to clarify the differences between the mutations identified in NS and leukemia, we examined the phosphatase activity of 14 mutants of SHP-2. We identified nine mutations, including a novel F71I mutation, in 16 of 41 NS patients and two mutations, including a novel G503V mutation, in three of 29 patients with leukemia. Immune complex phosphatase assays of individual mutants transfected in COS7 cells showed that ten mutants identified in NS and four mutants in leukemia showed 1.4-fold to 12.7-fold increased activation compared with wild-type SHP-2. These results suggest that the pathogenesis of NS and leukemia is associated with enhanced phosphatase activity of mutant SHP-2. A comparison of the phosphatase activity in each mutant and a review of previously reported cases showed that high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 was significantly associated with leukemogenesis.

Adolescent↗
PubMed2006

Activating PTPN11 mutations play a minor role in pediatric and adult solid tumors.

The PTPN11 gene encodes SHP-2, a widely expressed cytoplasmic protein tyrosine phosphatase functioning as a signaling transducer. Germ-line PTPN11 mutations cause Noonan syndrome (NS), a developmental disorder characterized by an increased risk of malignancies. Recently, a novel class of activating mutations in PTPN11 has been documented as a somatic event in a heterogeneous group of leukemias. Because of the relatively higher prevalence of certain solid tumors in children with NS and the positive modulatory function of SHP-2 in RAS signaling, a wider role for activating PTPN11 mutations in cancer has been hypothesized. Here, we screened a number of solid tumors, including those documented in NS or in which deregulated RAS signaling occurs at significant frequency, for PTPN11 mutations. No disease-associated mutation was identified in rhabdomyosarcoma (n = 13), neuroblastoma (n = 32), melanoma (n = 50), thyroid (n = 85), and colon (n = 48) tumors; a novel missense change, promoting an increased basal phosphatase activity of SHP-2, was observed in one glioma specimen. Our data document that deregulated SHP-2 function does not represent a major molecular event in pediatric and adult tumors, further supporting our previous evidence indicating that the oncogenic role of PTPN11 mutations is cell-context specific.

Adult↗
PubMed2004

Spontaneous hemopneumothorax: a rare but life-threatening entity.

OBJECTIVES: Spontaneous hemopneumothorax (SHP) is a rare disorder, complicating 1-12% of patients with spontaneous pneumothorax. We conducted a retrospective review in order to study this potentially life-threatening condition and compared our experience with reports in the international literature. METHODS: Between 1970 and 2000, 3489 patients were treated in our department with spontaneous pneumothorax. Seventy-one of them (2%), 63 men and 8 women, aged between 13 and 80 years, presented SHP. Patients presented dyspnea and chest pain. In the majority, chest X-ray confirmed the diagnosis of hydropneumothorax. RESULTS: All our patients were initially treated with tube thoracostomy or thoracocentesis. Conservative treatment alone was effective in 16 cases (22.5%). Among the other 55 patients (77.5%), 28 (39.4%) were operated on an emergency basis since they were in shock, while 27 (38%) were electively led to surgery for clot evacuation, resection of the bulla, ligation of the adhesion between the parietal and visceral pleura and irrigation of the pleural cavity through thoracotomy. Postoperative course was uneventful and the patients were discharged from the hospital within 7-12 days. CONCLUSIONS: (1) SHP is a rare clinical entity that can lead to potentially life-threatening complications. (2) Early thoracotomy should be considered once the diagnosis of SHP is confirmed.

Adolescent↗
PubMed2005

Germ-line and somatic PTPN11 mutations in human disease.

Reversible protein tyrosyl phosphorylation of cell surface receptors and downstream intracellular transducers is a major regulatory mechanism used to modulate cellular responses to extracellular stimuli, and its deregulation frequently drives aberrant cell proliferation, survival and/or differentiation. SHP-2 is a cytoplasmic Src-homology 2 domain-containing protein tyrosine phosphatase that plays an important role in intracellular signaling and is required during development and hematopoiesis. Germ-line missense mutations in PTPN11, the gene coding SHP-2, have been discovered as a major molecular event underlying Noonan syndrome, an autosomal dominant trait characterized by short stature, dysmorphic facies, and congenital heart defects, as well as in other closely related developmental disorders. More recently, a distinct class of missense mutations in the same gene has been identified to occur as a somatic event contributing to myeloid and lymphoid malignancies. This review focuses on the role of SHP-2 in signal transduction, development and hematopoiesis, as well as on the consequences of SHP-2 gain-of-function.

Animals↗
PubMed2005

Anti-CD33 monoclonal antibodies enhance the cytotoxic effects of cytosine arabinoside and idarubicin on acute myeloid leukemia cells through similarities in their signaling pathways.

OBJECTIVE: Chemotherapy agents (CA) such as cytosine arabinoside (ara-C), idarubicin (IDA), and etoposide (VP-16) are widely used in the treatment of acute myeloid leukemia (AML) However, their effects on signaling pathways leading to cytotoxicity have only been described recently. Ligation of the leukemia-associated antigen CD33 by anti-CD33 monoclonal antibody (mAb) also results in signaling events that induce a downregulation of cell growth. We examined the possibility that anti-CD33 mAb and CA might cooperate in mediation of growth inhibition in primary AML samples and AML cell lines. MATERIALS AND METHODS: We investigated two AML cells lines and 14 primary AML samples for their proliferative response ((3)H-thymidine incorporation), colony formation, and biochemical (Western blot analysis) to anti-CD33 mAb treatment combined with chemotherapy agents. RESULTS: CD33 ligation induced a significant increase in ara-C- or IDA- but not VP-16-or Bryostatin-mediated inhibition of proliferation and colony formation. Ara-C and IDA induced SHP-1 and SHP-2 protein tyrosine phosphatase (PTPs) phosphorylation and Lyn/SHP-1 complex formation, while VP-16 and Bryostatin did not. CD33 ligation, however, mediated phosphorylation of these PTPs and Syk/SHP-1 complex formations. Combined treatment of AML cells by ara-C or IDA with anti-CD33 mAb resulted in higher levels of SHP-1 phosphorylation. Reduction in SHP-1 by short interfering RNA abrogated these effects. CONCLUSION: These data suggest that combined incubation of leukemia cells with anti-CD33 mAb and ara-C or IDA, but not VP-16 or Bryostatin, independently triggers similar events in the downstream signaling cascade, and therefore leads to additive antiproliferative effects and enhanced cytotoxicity.

Antibodies, Monoclonal↗
PubMed2004

Plastic and elastic properties of the systems interstratified clay-water-electrolyte-xanthan.

The present study concerns the rheological behavior of the Jebel Shemsi clay dispersions (Shp). Shp is an interstratified illite/smectite clay from southern Tunisia. The influences of clay concentration, NaCl, and xanthan-a semirigid polymer-on the yield stress, the elastic modulus, and the xanthan adsorption were investigated. The sol-gel transition and the scale laws of rheometric properties are established. Progressive addition of NaCl to the clay dispersions decreases the thickness of the diffuse double layer, which makes the system rigid, increasing the yield and the elastic modulus. In the presence of xanthan, the negative surface charges become higher and the repulsive interparticle interactions increase; consequently the yield and the elastic modulus increase. The xanthan adsorption on the clay particle surface increases slightly with the NaCl concentration. The particle aggregation due to the salt and the particle dispersion due to the polymer are observed. The behavior of this interstratified clay is compared to that found for pure smectite. The 15% illite stratified with smectite in the Shp clay does not change the gels' rheological properties significantly. Meanwhile the amount of Shp clay needed to obtain a gel is more important than in the case of a pure smectite.

Journal Article↗
PubMed2005

Aging alters vascular mechanotransduction: pressure-induced regulation of p70S6k in the rat aorta.

Physical forces are important regulators of vascular structure and function though it is unknown how aging may affect the ability of the vasculature to respond to mechanical stimuli. We investigated the pressure-induced activation of ribosomal S6-kinase (p70S6k) and its pathway-related proteins (Akt, GSK-3beta, SHP-2, PTEN) in aortae from young adult (6 month), aged (30 month), and very aged (36 month) Fischer 344 x Brown Norway F1 hybrid rats. With aging, the aortic tissue content of Akt. SHP-2, and PTEN was significantly increased while total p70S6k and GSK-3beta were unchanged. By comparison, the basal phosphorylation of p70S6k at Thr 389 and Thr 421/Ser 424 was increased ( approximately 40%) and unchanged, respectively, while Akt decreased (approximately 37%), GSK-3beta was unchanged, SHP-2 increased (approximately 73.5%), and PTEN increased (approximately 120%) in the aortae of very aged rats. Acute pressurization of aortae resulted in similar increases in phosphorylation of Akt among the different age groups. By comparison, pressure-induced phosphorylation of p70S6k at Thr 389, GSK-3beta and SHP-2 decreased; whereas, PTEN dephosphorylation was increased in 36-month versus 6-month aortae. The results indicate marked alterations in the p70S6k signaling pathway with aging. The implications of these findings on age-associated vessel remodeling are discussed.

Aged↗
PubMed1992

Impairment of lung diffusion capacity in Schönlein-Henoch purpura.

Twenty-nine children with typical Schönlein-Henoch purpura (SHP) were tested at the initial phase of the disease for respiratory function. Of the 29 patients, 28 had a decrease of lung transfer for carbon monoxide (TLCO) as measured by a steady-state method. Lung volumes and blood gas values were normal; slight radiologic signs of interstitial lung involvement were observed in 18 of 26 patients. There was a decrease in TLCO to 56.8% of normal values for height and gender and to 58.5% when normal values were volume-adjusted to functional residual capacity. In 19 of 25 patients, TLCO measurements were performed at 3-month intervals during follow-up. In all cases, normalization of TLCO values was observed only after complete clinical recovery from SHP. All children with persisting symptoms, even limited to microscopic hematuria or slight proteinuria, had low TLCO values. In one patient low TLCO during follow-up preceded a late relapse of SHP in the form of acute nephritic disease with characteristic IgA deposits on renal biopsy. We conclude that low TLCO in SHP is probably related to alteration of the alveolar-capillary membrane by circulating immune complexes. This noninvasive technique may be useful in diagnosis, and during the follow-up of the disease as an early indicator of reactivation.

Carbon Monoxide↗
PubMed2003

Decreased expression of Src homology 2 domain-containing protein tyrosine phosphatase 1 reduces T cell activation threshold but not the severity of experimental autoimmune myasthenia gravis.

Myasthenia gravis (MG) and its murine model experimental autoimmune myasthenia gravis (EAMG) are T cell-dependent, antibody-mediated autoimmune diseases. Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a cytosolic tyrosine phosphatase that is involved in regulating the T cell activation cascade from signals initiated through the TCR. To study the role of SHP-1 in EAMG pathogenesis, we immunized C57BL/6 (B6) mice heterozygous for deletion of the SHP-1 gene (me(v+/-)) and their littermate wild type B6 mice with torpedo acetylcholine receptor (TAChR). T cell proliferation and IFNgamma production were significantly increased in B6.me(v+/-) mice after immunization with AChR compared to that of wild type littermates. However, clinical incidence and severity of the disease were not changed. There also were no significant differences in AChR-specific antibodies produced between wild type and me(v+/-) mice. These data suggest that deficiency in SHP-1 expression does decrease the activation threshold of autoreactive T cells in EAMG, but the increased frequency of autoreactive T cells does not aggravate EAMG in terms of clinical score, incidence, or antibody titers.

Animals↗
PubMed2003

Use of RNA interference to investigate gene function in the human filarial nematode parasite Brugia malayi.

We describe the successful use of the reverse genetic technique RNA interference (RNAi) to investigate gene function in the human filarial nematode parasite Brugia malayi. We used fluorescently labelled double stranded RNA (dsRNA) to demonstrate that 300 bp molecules are able to enter adult females in culture while they remain excluded from microfilariae (mf). We have developed an optimised microvolume culture system to allow the exposure of parasites to high concentrations of dsRNA for extended periods. Culturing of adult female parasites in this system for 24h does not significantly reduce parasite lifespan or mf release in culture. Three B. malayi genes, beta-tubulin (Bm-tub-1), RNA polymerase II large subunit (Bm-ama-1) and B. malayi mf sheath protein 1/mf22 (Bm-shp-1) were targeted by soaking adult female B. malayi in dsRNA complementary to these transcripts in the optimised culture system. Targeting of the two housekeeping genes Bm-tub-1 and Bm-ama-1 led to a reduction in the levels of their transcripts, as assessed by reverse transcriptase coupled PCR (RT-PCR), and resulted in parasite death in culture. In contrast, targeting of the Bm-shp-1 gene was not lethal to adult females in culture. A marked reduction in mf release was observed for shp-1 RNAi parasites compared to controls and in addition 50% of mf released did not have fully elongated sheaths. This "short" phenotype correlated with the loss of the stockpiled shp-1 transcript from developing mf in treated adult female gonads. From these data we conclude that RNAi may be a useful method for assessment of drug target potential of genes identified in filarial gene discovery projects.

Alternative Splicing↗
PubMed2000

Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.

The catabolism of cholesterol into bile acids is regulated by oxysterols and bile acids, which induce or repress transcription of the pathway's rate-limiting enzyme cholesterol 7alpha-hydroxylase (CYP7A1). The nuclear receptor LXRalpha binds oxysterols and mediates feed-forward induction. Here, we show that repression is coordinately regulated by a triumvirate of nuclear receptors, including the bile acid receptor, FXR; the promoter-specific activator, LRH-1; and the promoter-specific repressor, SHP. Feedback repression of CYP7A1 is accomplished by the binding of bile acids to FXR, which leads to transcription of SHP. Elevated SHP protein then inactivates LRH-1 by forming a heterodimeric complex that leads to promoter-specific repression of both CYP7A1 and SHP. These results reveal an elaborate autoregulatory cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism.

Animals↗