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At least 1,081 records · Page 60Linked to original sources
PubMed2005

MIBI scintigraphy, indicators of cell proliferation and histology of parathyroid glands in uraemic patients.

BACKGROUND: Although scintigraphy with (99m)Tc-sestamibi (MIBI) has been used to localize parathyroid glands prior to surgery for hyperparathyroidism, using it to evaluate parathyroid function remains controversial. The purpose of this study was to evaluate the possible association of MIBI uptake with gland weight, histological pattern and proliferative activity of parathyroid cells. METHODS: We studied 18 patients with secondary hyperparathyroidism (SHP); mean age 38+/-3 years, 55% female, mean time on haemodialysis 7.7+/-0.9 years. All patients had parathyroidectomy (PTx). The weights of the removed glands were estimated, and parathyroid hyperplasia was classified as diffuse (n = 28) or nodular (n = 29). The expression of proliferative cell nuclear antigen (PCNA) was evaluated by immunohistochemistry. Before PTx, all patients underwent MIBI evaluation and were categorized using a 0-3 uptake scoring system. Low uptake (scores of 0 and 1) was seen in 39 glands and high uptake (scores of 2 and 3) in 18. RESULTS: Estimated gland weights, percentage of nodular hyperplasia and PCNA expression were greater in glands with high MIBI scores than in those with low scores (P<0.01). In glands with nodular hyperplasia, PCNA expression was higher (318+/-66 cells/mm2) than in those with diffuse hyperplasia (104+/-16 cells/mm2; P<0.001). CONCLUSIONS: High MIBI scores were associated with high estimated gland weight, degree of cell proliferation and presence of nodular hyperplasia. MIBI scintigraphy is useful in clinical practice for localizing parathyroid glands, and it could guide the management of SHP by indicating the degree of its severity.

Adult↗
PubMed2000

RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia.

The SH2 domain-containing tyrosine phosphatase PTPN6 (SHP-1, PTP1C, HCP) is a 68 kDa cytoplasmic protein primarily expressed in hematopoietic cell development, proliferation and receptor-mediated mitogenic signaling pathways. By means of direct dephosphorylation, it down-regulates a broad spectrum of growth-promoting receptors, including the Kit tyrosine kinase, activated to elicit a prominent cascade of intracellular events by stem cell factor binding. The pivotal contribution of PTPN6 in modulating myeloid cell signaling has been revealed by the finding that shp-1 mutation is responsible for the overexpansion and inappropriate activation of myelomonocytic populations in motheaten (me/me) and motheaten viable (me(v)/me(v)) mice. Association of PTPN6 with c-Kit and negative modulation of the myeloid leukocyte signal transduction pathways prompted us to examine the expression of the protein tyrosine phosphatase PTPN6 gene in CD34(+)/CD117(+) blasts from acute myeloid leukemia patients. We identified and cloned cDNAs representing novel PTPN6 mRNA species, derived from aberrant splicing within the N-SH2 domain leading to retention of intron 3. Sequence analysis of cDNA clones revealed multiple A-->G editing conversions. The editing of PTPN6 mRNA mainly occurred as an A-->G conversion of A(7866), which represents the putative branch site in IVS3 of PTPN6 mRNA. Evidence that editing of A(7866) abrogates splicing has been obtained in vitro by using an edited clone and its backward clone generated by site-directed mutagenesis. The level of the aberrant intron-retaining splice variant, evaluated by semi-quantitative RT-PCR, was lower in CD117(+)-AML bone marrow mononuclear cells at remission than at diagnosis, suggesting the involvement of post-transcriptional PTPN6 processing in leukemogenesis.

Acute Disease↗
PubMed1998

Genomic structures and chromosomal location of p91, a novel murine regulatory receptor family.

Recently, we found a novel murine cell-surface glycoprotein, designated as p91, expressed mainly in myeloid cells such as macrophages and mast cells. The molecule has six immunoglobulin-like extracellular domains, a transmembrane segment, and a cytoplasmic tail containing four immunoreceptor tyrosine-based inhibition motif (ITIM) or ITIM-like sequences, resembling the structural features of human killer-cell inhibitory receptors (KIR). Here we show that p91 comprises a polymorphic gene family, harboring one potent inhibitory-type p91 and at least two other p91 genes. Tyrosine-phosphorylated, but not nonphosphorylated, synthetic peptides matching the third ITIM and the fourth ITIM-like sequences, respectively, found in the cytoplasmic portion of p91A, the sole inhibitory-type p91, were associated with the tyrosine phosphatases, SHP-1 and SHP-2. In addition, the phosphotyrosyl peptide matching the third ITIM sequence also bound the inositol 5-phosphatase, SHIP. These results support the notion that p91A may function as an inhibitory cell-surface molecule against cell activation. The p91 genes were shown to be clustered in the proximal region of mouse chromosome 7, a syntenic position of human chromosome 19 where the genes for the KIR family are found. A human cDNA clone cross-hybridizing to a murine p91 probe was isolated from a human spleen cDNA library, and was found to code for a molecule quite similar to members of the immunoglobulin-like transcript (or ILT) family. The gene was found to be located on human chromosome 19q13.3-13.4. These results establish the existence of a novel set of potent regulatory receptors in mouse and man, similar but different from the KIR family.

Amino Acid Sequence↗
PubMed2004

Iodine deficiency in Papua New Guinea (sub-clinical iodine deficiency and salt iodization in the highlands of Papua New Guinea).

Data on the status about iodine nutrition in children in Papua New Guinea (PNG) are scarce. This study attempts to determine the mean daily per capita consumption of salt, the iodine content of salt in the households and retail shops and the urinary iodine concentration in children (6-12 years) in Hella Region, Southern Highland Province (SHP), PNG. The mean daily consumption of salt was 2.62 +/- 1.29 g. The iodine content of salt was >30 p.p.m. in 95 per cent of households and 100 per cent of retail shops. The median urinary iodine concentration of 48.0 mg/l for all the children indicates moderate iodine deficiency. The median urinary iodine concentrations for the male (67.0 mg/l) and female (44.0 mg/l) children indicate mild and moderate iodine deficiency, respectively. 68.42 per cent of the male and 81.82 per cent of the female children have urinary iodine concentration <100 mg/l, indicating that iodine deficiency is a potential public health problem in the Hella region. These results indicate a need for further assessment of the implementation of the universal salt iodization strategy for the elimination of iodine deficiency in the SHP, PNG.

Child↗
PubMed1998

Migration, stem shape, and surface finish in cemented total hip arthroplasty.

In many recent publications it was suggested that the amount of early subsidence of a femoral stem in total hip arthroplasty is indicative for later revision. In this article it is argued that stems can be designed according to alternative objectives, resulting in different shapes and surface roughness, each producing its own characteristic postoperative subsidence pattern. It was investigated whether these inherent subsidence patterns can be estimated in preclinical testing. For that purpose two stems, both without a collar, relying on cement fixation only, were compared regarding their stress transfer, migration, and induced micromotion behavior. Finite element analysis, cyclic bench testing of substitute bone reconstructions, and clinical radiostereophotogrammetric analysis were applied. The stems investigated were the Exeter, which is assumed to be a force closed fixation design, relying on subsidence under load as a method of maintaining stability, and the SHP, as a shape closed fixation design, meant to be contained by the cement mantle. Both designs were true to their design concepts in the analyses, in the sense that migrations and micromotions of the Exeter stems far exceeded those of the SHP stems. It was found that preclinical studies such as finite element analysis or bench tests give reasonable indications of in vivo postoperative behavior. It is concluded that early clinical migration values should be considered relative to stem shape and surface finish, when prediction of later revision probability is the issue.

Aged↗
PubMed1980

Spontaneous intestinal perforation in Schönlein-Henoch purpura.

Schönlein-Henoch purpura (SHP) continues to present diagnostic and therapeutic challenges to internists and to surgeons. Indications for operation in this entity are solely for intussusception, ischemic bowel necrosis, and frank bowel perforation. We present two recent cases of spontaneous small bowel perforation in SHP and analyze the previously reported cases. Spontaneous intestinal perforation is often heralded by increase in rectal blood loss, even frank melena, and a worsening or unresponsive abdominal picutre such as progressive distention and loss of bowel sounds. Perforations, usually ileal, may be accompanied by intussusception.

Humans↗
PubMed1995

Purification and characterization of the serotype-specific polysaccharide antigen of Trichosporon cutaneum serotype II: a disease-related antigen of Japanese summer-type hypersensitivity pneumonitis.

Summer-type hypersensitivity pneumonitis (SHP) is a unique type of hypersensitivity pneumonitis and the most prevalent in Japan. Our previous study clarified that the causative agent of the disease is Trichosporon cutaneum, and that the patients with SHP have high titres of antibodies against the serotype-specific antigen of polysaccharide nature which exist in the high molecular weight fraction of the culture supernatant of the yeast. In this study, we purified the serotype-specific antigen of serotype II T. cutaneum by gel filtration and affinity chromatography using a monoclonal antibody, D-8, specific for a high molecular weight antigen of serotype II T. cutaneum, and elucidated the structure of the antigen. This affinity-purified antigen was shown to be an essentially acidic polysaccharide comprising mannose, xylose, and glucuronic acid (6:44:4.7). Chemical analysis showed that this polysaccharide antigen contains a (1-3)-linked mannan backbone attached with short side chains of (1-4)-linked mannose and a small proportion of (1-2)-linked xylose residues by substituting the 2- or 4-positions of the (1-3)-linked mannose residues of the main chain. Approximately one-fifth of the side chains were terminated with glucuronic acid residues. The antigenic epitope of the serotype-specific antigen was shown to involve the terminal glucoronic acid residues as revealed by immunodiffusion test and sandwich enzyme-linked immunosorbent assay using monoclonal antibody D-8.

Alveolitis, Extrinsic Allergic↗
PubMed1997

The role of tyrosine phosphorylation in proliferation and maturation of erythroid progenitor cells--signals emanating from the erythropoietin receptor.

Red blood cells arise continuously from pluripotent stem cells which mature and become functionally specialized upon commitment to the erythroid lineage. In mammals, the key regulator of this process is the hormone erythropoietin (EPO). Hormone binding to the cognate receptor, the erythropoietin receptor (EPO-R), causes receptor homodimerization and transiently triggers tyrosine phosphorylation within target cells. Although the EPO-R lacks intrinsic enzymatic activity it couples, presumably sequentially, to the protein tyrosine kinase receptor c-KIT and the cytosolic protein tyrosine kinase JAK2. Signaling through the EPO-R is promoted by tyrosine phosphorylation of the cytosolic domain and the recruitment of secondary signaling molecules such as the lipid kinase inositolphospholipid 3-kinase (phosphatidylinositol 3-kinase) and protein tyrosine phosphatase SHP-2 to the activated receptor. Complex formation of the activated EPO-R with the protein tyrosine phosphatase SHP-1 terminates signaling. In primary fetal liver cells redundant signals emanating from phosphotyrosine residues in the EPO-R support formation of erythroid colonies in vitro. However, since the last tyrosine residue in the cytosolic domain of the EPO-R, Y479, uniquely supports in the absence of other tyrosine residues an almost normal level of colony-forming unit-erythroid (CFU-E) colony formation, Y479 represents one of the key residues required in vivo for erythroid proliferation and differentiation. The signal emanating from Y479 involves sequential EPO-induced recruitment of phosphoinositol lipid 3-kinase to the EPO-R and activation of mitogen-activated-protein(MAP)kinase activity. The MAP-kinase signaling cascade could serve as an intracellular switch integrating signals mediated by several phosphotyrosine residues in the cytosolic domain of the EPO-R and provide a possible explanation for partial redundancy in signaling.

Animals↗
PubMed2004

Collaborative field study on the utility of a BDD factor VIII concentrate standard in the estimation of BDDr Factor VIII:C activity in hemophilic plasma using one-stage clotting assays.

Advances in production technologies of factor (F)VIII concentrates during the last two decades has resulted in very pure and safe products. In assessment of recombinant FVIII:C, inconsistent assay values are found comparing one-stage assays with two-stage (e.g. amidolytic) methods. Such discrepancies have been quite prominent in the case of a B-domain deleted recombinant FVIII (BDDrFVIII, ReFacto). In order to alleviate this assay variance, a product-specific reference standard [the ReFacto Laboratory Standard (RLS)], was established for laboratory use with either one-stage clotting or chromogenic substrate assays for the measurement of FVIII:C in ReFacto-containing patient samples. The primary objective of the current study was to assess, under field laboratory conditions, the accuracy and precision of the one-stage clotting assay for the determination of FVIII:C in ReFacto-containing samples employing the new concentrate standard. A secondary goal was to assess whether use of the RLS would minimize the discrepancy between one-stage clotting and chromogenic substrate assays. Thirty-one clinical laboratories worldwide participated in the study of severe-hemophilic plasma (SHP) samples that had been spiked with ReFacto to target levels of 0.9, 0.6 and 0.2 IU mL(-1). FVIII:C levels were determined against both the RLS and the local in-house plasma standard (IHS). The results showed good agreement between laboratories in FVIII:C levels obtained by one-stage clotting assays utilizing the RLS, and a good degree of accuracy was found compared with the intended target values. Consistent with previously published data, a discrepancy of approximately 30% was observed between one-stage clotting and chromogenic potencies when the IHS was used as the calibrator. The discrepancy between one-stage and chromogenic assay methodologies was significantly reduced when the RLS was employed as calibrator in the one-stage assay. In conclusion, the study demonstrates that accurate and precise FVIII:C results can be obtained for ReFacto-containing SHP samples by clinical laboratories using a product-specific standard in one-stage clotting assays. In addition, the product-specific reference standard significantly reduced the discrepancy between the one-stage clotting and the chromogenic substrate assay for ReFacto.

Blood Coagulation↗
PubMed1997

Killer cell inhibitory receptors: diversity, specificity, and function.

NK cells selectively kill target cells that fail to express self-MHC class I molecules. This selective killing results from a balance between inhibitory NK receptors specific for MHC class I molecules and activating receptors that are still largely unknown. Isolation of molecular clones for the human killer cell inhibitory receptors (KIR) revealed that KIR consist of a family of molecules with Ig ectodomains and cytoplasmic tails of varying length. Soluble complexes of KIR and HLA-C molecules established that KIR recognizes and binds to its ligand as an autonomous receptor. A functional expression system in human NK clones demonstrated that a single KIR can provide both recognition of MHC class I and delivery of a dominant negative signal to the NK cell. Functional evidence has been obtained for a role of the tyrosine phosphatase SHP-1 in KIR-mediated inhibition. The presence of a conserved motif used to recruit and activate SHP-1 in the cytoplasmic tail of KIR and of the mouse Ly-49 inhibitory receptor (otherwise structurally unrelated to KIR) represents an interesting case of evolutionary convergence. Furthermore, the motif led to the identification of other receptors with inhibitory potential, including a type I Ig-like receptor shared by mouse mast cells and NK cells.

Amino Acid Sequence↗
PubMed1988

Cl- - and K+-dependent inhibitory postsynaptic potentials evoked by interneurones of the rat lateral geniculate nucleus.

1. Hyperpolarizing potentials evoked by electrical stimulation of the optic tract were studied in projection cells of the rat dorsal lateral geniculate nucleus (LGN) in vitro. In the same cells the effects of gamma-amino butyric acid (GABA), baclofen and acetylcholine (ACh) were also investigated. 2. In the majority of cells a short- (SHP) (34 ms) and a long-lasting (LHP) (240 ms) hyperpolarizing potential could be recorded in the presence and in the absence of a preceding EPSP. They were blocked by tetrodotoxin (1 microM) and were more sensitive than the monosynaptic EPSP to a low-Ca2+-high-Mg2+ solution. 3. The SHP was associated with a marked decrease (75%) in input resistance, was blocked by bicuculline (1-100 microM) and its reversal potential (-67 mV) was dependent on the extracellular Cl- concentration. 4. The LHP was associated with a smaller decrease (45%) in input resistance and its reversal potential (-76 mV) was dependent on the extracellular K+ concentration. It was increased by bicuculline (100% at 50 microM) and nipecotic acid (30% at 10 microM), blocked by Ba2+ (1 mM), and unaffected by eserine (1-10 microM), neostigmine (1-10 microM) or by recording with EGTA-filled electrodes. In the presence of bicuculline, a single LHP was able to evoke, as a rebound response, a low-threshold Ca2+ spike that was, however, not followed by another LHP (or any other long-lasting hyperpolarization). 5. Ionophoretic applications of GABA evoked in the same cell a Cl- -dependent hyperpolarization (reversal potential: -65 mV) and/or depolarization, both of which were associated with a marked decrease (91%) in input resistance and abolished by bicuculline. GABA was also able to evoke a bicuculline-insensitive, K+-dependent hyperpolarization that had a reversal potential of -75 mV and was associated with a smaller decrease (43%) in input resistance. 6. Baclofen, applied by ionophoresis, pressure ejection or in the perfusion medium (1-100 microM), produced a hyperpolarization that had a reversal potential of -79 mV and was associated with a decrease (45%) in input resistance. 7. In the majority of cells (thirty-seven out of forty) ACh evoked a slow depolarization and only in three cells a hyperpolarization which had a reversal potential of -80 mV.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed2005

Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis.

The farnesoid X receptor (FXR), an endogenous sensor for bile acids, regulates a program of genes involved in bile acid biosynthesis, conjugation, and transport. Cholestatic liver diseases are a group of immunologically and genetically mediated disorders in which accumulation of endogenous bile acids plays a role in the disease progression and symptoms. Here, we describe the effect of 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic bile acid derivative and potent FXR ligand, in a model of cholestasis induced by 5-day administration of 17alpha-ethynylestradiol (E(2)17alpha) to rats. The exposure of rat hepatocytes to 1 microM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7alpha-hydroxylase (cyp7a1), oxysterol 12beta-hydroxylase (cyp8b1), and Na(+)/taurocholate cotransporting peptide (ntcp). In vivo administration of 6-ECDCA protects against cholestasis induced by E(2)17alpha. Thus, 6-ECDCA reverted bile flow impairment induced by E(2)17alpha, reduced secretion of cholic acid and deoxycholic acid, but increased muricholic acid and chenodeoxycholic acid secretion. In vivo administration of 6-ECDCA increased liver expression of Shp, bsep, multidrug resistance-associated protein-2, and multidrug resistance protein-2, whereas it reduced cyp7a1 and cyp8b1 and ntcp mRNA. These changes were reproduced by GW4064, a synthetic FXR ligand. In conclusion, by demonstrating that 6-ECDCA protects against E(2)17alpha cholestasis, our data support the notion that development of potent FXR ligands might represent a new approach for the treatment of cholestatic disorders.

Animals↗
PubMed2006

The human organic cation transporter-1 gene is transactivated by hepatocyte nuclear factor-4alpha.

The organic cation transporter-1 (OCT1) mediates the hepatocellular uptake of cationic drugs and endobiotics from sinusoidal blood. The uptake rates of these compounds may depend on OCT1 expression level. Because little is known about the regulation of the human OCT1 (hOCT1) gene, we characterized the hOCT1 promoter with respect to DNA-response elements and their binding factors. By computer analysis, we identified two adjacent putative DNA-response elements for the liver-enriched homodimeric nuclear receptor hepatocyte nuclear factor-4alpha (HNF-4alpha) in the hOCT1 promoter. Each element is of the direct repeat (DR)-2 format, containing directly repeated hexamers separated by two bases. In electrophoretic mobility shift assays, both elements directly interacted with HNF-4alpha. A luciferase reporter construct containing the hOCT1 promoter was strongly activated by HNF-4alpha in transiently transfected Huh7 cells. Site-directed mutagenesis of either DR-2 element alone or in combination severely decreased the HNF-4alpha-mediated activation of the hOCT1 promoter, indicating that both elements are functionally important. Because HNF-4alpha is a known target for bile acid-mediated suppression of transcription, we studied whether chenodeoxycholic acid (CDCA) suppresses hOCT1 gene expression by inhibiting HNF-4alpha-mediated transactivation. Treatment of cells with CDCA could indeed suppress the activation of the endogenous hOCT1 gene by HNF-4alpha. In addition, bile acid-inducible transcriptional repressor, small heterodimer partner (SHP), inhibited activation of the reporter-linked hOCT1 promoter and of the endogenous hOCT1 gene by HNF-4alpha. In conclusion, the hOCT1 gene, encoding an important drug transporter in the human liver, is activated by HNF-4alpha and suppressed by bile acids via SHP.

Base Sequence↗
PubMed2005

The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes.

The farnesoid X receptor (FXR) is a nuclear receptor that functions as an endogenous sensor for bile acids (BAs). FXR is bound to and activated by bile acid, and chenodeoxycholic acid (CDCA) is the natural most active ligand. Upon activation, FXR heterodimerizes with the 9-cis retinoic X receptor (RXR) and regulates genes involved in cholesterol and BA homeostasis. 6-Ethyl CDCA (6-ECDCA) is a synthetic BA that binds FXR and induces gene transcription by recruiting coactivators, such as steroid receptor coactivator-1, with histone acetyltransferase activity. In addition to acetylation, histone methylation is critically involved in regulating eukaryotic gene expression. In the present study, we demonstrated that 6-ECDCA activates FXR to interacts with Protein Arginine Methyl-Transferase type I (PRMT1), which induces up-regulation of bile salt export pump (BSEP) and the small heterodimer partner (SHP) mRNA expression and causes a down-regulation of P450 cholesterol 7alpha-hydroxylase and Na(+) taurocholate cotransport peptide genes. Chromatin immunoprecipitation assay suggests that 6-ECDCA induces both the recruitment of PRMT1 and the H4 methylation to the promoter of BSEP and SHP genes. We also provide evidence that a methyltransferase inhibitor blocks the activation of FXR-responsive genes. Our results indicate that histone methylation, similar to acetylation, regulates transcriptional activation of genes involved in cholesterol and BAs homeostasis.

Cell Line↗
PubMed2006

PirB restricts ocular-dominance plasticity in visual cortex.

Experience can alter synaptic connectivity throughout life, but the degree of plasticity present at each age is regulated by mechanisms that remain largely unknown. Here, we demonstrate that Paired-immunoglobulin-like receptor B (PirB), a major histocompatibility complex class I (MHCI) receptor, is expressed in subsets of neurons throughout the brain. Neuronal PirB protein is associated with synapses and forms complexes with the phosphatases Shp-1 and Shp-2. Soluble PirB fusion protein binds to cortical neurons in an MHCI-dependent manner. In mutant mice lacking functional PirB, cortical ocular-dominance plasticity is more robust at all ages. Thus, an MHCI receptor is expressed in central nervous system neurons and functions to limit the extent of experience-dependent plasticity in the visual cortex throughout life. PirB is also expressed in many other regions of the central nervous system, suggesting that it may function broadly to stabilize neural circuits.

Aging↗
PubMed2001

Intracellular signaling by the killer immunoglobulin-like receptors and Ly49.

Once thought to be promiscuous killers, it is now known that natural killer (NK) cells possess an elaborate array of receptors that regulate NK cytotoxic and secretory functions upon interaction with target cell MHC class I proteins. These receptors, known as killer cell immunoglobulin-like receptors (KIRs) in humans, and Ly49 receptors in the mouse, have become the focus of intense study in an effort to discern the underlying biology of these large receptor families. These receptor families include both inhibitory and activating receptors. Interrogation of a target expressing KIR ligands leads to coengagement of the inhibitory receptor with as-yet poorly defined activation receptors. Kinases activated during engagement mediate the phosphorylation of the KIR or Ly49 cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The phosphorylated ITIMs serve as efficient recruitment points for the cytosolic protein tyrosine phosphatases, SHP-1 and SHP-2, resulting in the dephosphorylation of substrates critical for cellular activation. In contrast, some KIRs and Ly49s lack the ITIM and possess a charged residue in their transmembrane domains that mediates interaction with the DAP12 signal transduction chain. DAP12 uses its cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM) to mediate cellular activation. Engagement of a DAP12 coupled KIR or Ly49 results in phosphorylation of DAP12, and other key substrates, including the Syk tryosine kinase, phospholipase C, and c-Cbl. DAP12 activation then leads to the Mapk cascade and ultimately to enhanced degranulation, and production of cytokines and chemokines. Although the context in which inhibitory and activating KIR and Ly49s function is not yet known, the dissection of the activating and inhibitory signal transduction pathways should shed light on their method of integration into the activation sequela of NK cells. Ultimately, this work will lead to concrete understanding of the immunobiology of these seemingly antagonistic receptor systems.

Amino Acid Sequence↗
PubMed2005

Orchestration of aberrant epithelial signaling by Helicobacter pylori CagA.

Persistent colonization by Helicobacter pylori is the strongest risk factor for distal gastric adenocarcinoma, and H. pylori strains that harbor the cag pathogenicity island further augment cancer risk. The H. pylori cag island encodes a secretion system, and the product of the terminal gene in the island (CagA) is translocated into host epithelial cells after bacterial attachment, where it undergoes tyrosine phosphorylation by Src kinases and binds the eukaryotic phosphatase SHP-2. Higashi et al. now demonstrate that CagA-dependent SHP-2 activation leads to sustained activation of ERK (extracellular signal-regulated kinase), culminating in morphological changes that mimic unrestrained stimulation by growth factors. These data implicate the cag island as a key mediator of pathogenic epithelial responses that may heighten the risk for gastric cancer.

Adenocarcinoma↗