Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During Drosophila hindgut development, bowl, caudal/CDX, brachyenteron/Brachyury/TBX, fork head/FOX, drumstick, lines, and wingless/WNT play important roles. Drosophila bowl gene is homologous to Drosophila odd-skipped (odd) gene and odd-skipped related gene (sob). Here, human OSR1, related to Drosophila odd, was isolated using bioinformatics and cDNA-PCR. OSR1 was found to encode 266 amino-acid protein with three C2H2-type zinc fingers, a tyrosine phosphorylation site (Tyr 203), and several putative PXXP SH3 binding motifs. Three zinc fingers and a tyrosine phosphorylation site were conserved among human OSR1, OSR2, Drosophila odd, sob, and bowl. OSR1 showed 63.6% total amino-acid identity with OSR2. OSR1 gene consisting of three exons was located on human chromosome 2p24. OSR1 mRNA of 2.3-kb in size was detected in adult colon, small intestine, prostate, testis, and fetal lung. OSR1 mRNA was significantly up-regulated in a pancreatic cancer cell line MIA PaCa-2, and was weakly expressed in gastric cancer cell lines OKAJIMA, MKN45, pancreatic cancer cell lines PANC-1, BxPC-3, AsPC-1, PSN-1, Hs766T, and esophageal cancer cell line TE10. Among 10 cases of primary gastric cancer, OSR1 mRNA was up-regulated in 5 cases, and was down-regulated in 2 cases. This is the first report on molecular cloning and characterization of human OSR1.
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PMID:Molecular cloning and characterization of OSR1 on human chromosome 2p24. 1211 63

Helicobacter pylori is a bacterial pathogen specialised to colonise and persist the gastric mucosa and to cause severe gastroduodenal disease. A major disease-associated bacterial component is a type IV secretion system (TFSS) encoded by the cytotoxin-associated genes pathogenicity island (cagPAI). Among the multiple responses in H. pylori-infected epithelial cells, the induction of proinflammatory cytokines and chemokines, cell spreading and motility associated with the "hum mingbird" phenotype appear strictly dependent on the functional transporter complex in the cagPAI. H. pylori is also capable of occasionally entering epithelial cells and manipulates the host immune system for immune evasion. Attached bacteria actively translocate the CagA protein into epithelial cells by a TFSS-dependent process and translocated CagA undergoes tyrosine phosphorylation in the carboxy terminal EPIYA sequence repeat motif (Y-972) by kinases of the Src family. Furthermore, we have identified a novel TFSS in H. pylori involved in horizontal DNA-transfer. Host cell signalling events and cellular phenotypes provoked by the cagPAI, the investigation of mechanisms related to gastric cancer as well as the development of a Salmonella based live recombinant vaccine are in the focus of additional departmental activities.
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PMID:Helicobacter pylori type IV secretion, host cell signalling and vaccine development. 1252 29

Helicobacter pylori is the leading bacterial cause of food-borne illness worldwide and plays a major role in the development of chronic gastritis, peptic ulcer, and gastric cancer. Strains isolated from patients contain the cagA gene (cytotoxin-associated gene A) and produce the vacuolating cytotoxin VacA. VacA binding to specific high-affinity cell surface receptors was shown by using indirect immunofluorescence and flow cytometry; high-affinity toxin binding was necessary for cell intoxication. A 250-kDa receptor protein tyrosine phosphatase (RPTP) beta served as a receptor for VacA on AZ-521 cells. The overexpression of RPTP beta conferred VacA sensitivity on BHK-21 cells transfected with the RPTP beta cDNA, consistent with RPTP gamma acting as a receptor for VacA. Increased binding of acid- or alkali-activated VacA to RPTP gamma may alter its activity and possibly accelerate or inhibit dephosphorylation of tyrosine on cytosolic proteins. Understanding the pathological responses of wild type and RPTP gamma-deficient animal models may well provide valuable information regarding the mechanism of VacA toxicity.
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PMID:Protein tyrosine phosphatase beta, a receptor for Helicobacter pylori vacA toxin. 1252 31

Recent experiments have indicated that CagA of Helicobacter pylori is injected into epithelial cells via the type IV secretion system and undergoes tyrosine phosphorylation in cells and that translocated CagA binds the SRC homology 2 domain-containing tyrosine phosphatase (SHP-2). We investigated these phenomena in in vivo human gastric mucosa. Tyrosine-phosphorylated CagA and CagA-coimmunoprecipitated SHP-2 were detected in gastric mucosa from H. pylori-positive patients with atrophic gastritis and in noncancerous tissues from H. pylori-positive patients with early gastric cancer. In contrast, CagA was not detected in gastric mucosa with either intestinal metaplasia or cancer. Our results provide the first evidence that CagA is translocated into the gastric epithelial cells, receives tyrosine phosphorylation, and binds SHP-2 in in vivo human gastric mucosa. Deregulation of SHP-2 by CagA may play a role in the acquisition of a cellular-transformed phenotype at a relatively early stage of multistep gastric carcinogenesis.
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PMID:The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa. 1255 62

Signet-ring cell carcinomas are malignant dedifferentiated carcinomas, which are frequently found in the stomach. We previously demonstrated that a 200 kDa protein is often constitutively phosphorylated on tyrosine and bound to phosphatidylinositol 3-kinase (PI3-kinase) in signet-ring cell carcinoma cells. In this study, we purified the 200 kDa protein from an extract of NUGC-4 cells, a cell line of signet-ring cell carcinoma, and identified it as ErbB3. ErbB3 was found to be phosphorylated selectively in dedifferentiated adenocarcinoma cell lines among various gastric cancer cell lines. Expression of a constitutively active chimeric receptor consisting of ErbB2 and ErbB3 in HCC2998 cells, a highly differentiated adenocarcinoma cell line, revealed that the signaling triggered by phosphorylation of ErbB3 was important for dedifferentiated phenotypes such as loss of cell-cell interaction and high expression of MUC1/DF3 antigen, a marker of the malignant tumors. Taken together, activation of ErbB3 pathway may contribute to the development of dedifferentiated carcinomas.
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PMID:Activation of ErbB3-PI3-kinase pathway is correlated with malignant phenotypes of adenocarcinomas. 1261 54

Many protein tyrosine kinases are key regulators involved in cellular growth, differentiation, development, apoptosis and signal transduction pathways. Obtaining a comprehensive tyrosine-kinase expression profile in tumour cells is essential to learning more about their oncogenic potentials and responses to various chemotherapeutic reagents - such as retinoic acid, which has been shown to suppress the growth of gastric cancer cells and modulate gene expression. Expression of tyrosine kinases in retionic acid-treated cancer cells was investigated by reverse trancriptase-polymerase chain reaction (RT-PCR) and a novel restriction analysis of gene expression (RAGE) display technique. We first established comprehensive tyrosine-kinase profiles in different human gastric cancer cell lines. In cells treated with 9-cis-retinoic acid or all-trans-retinoic acid, we found that two PTKs (Eph and Hek5) appeared to be upregulated. In the present study, we demonstrate an efficient and simple RAGE approach for examining tyrosine kinases' expression in tumour cells and their alterations following drug treatments.
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PMID:Tyrosine-kinase expression profiles in human gastric cancer cell lines and their modulations with retinoic acids. 1267 5

The Src family of non-receptor protein tyrosine kinases plays critical roles in a variety of cellular signal transduction pathways, regulating such diverse processes as cell division, motility, adhesion, angiogenesis, and survival. Constitutively activated variants of Src family kinases, including the viral oncoproteins v-Src and v-Yes, are capable of inducing malignant transformation of a variety of cell types. Src family kinases, most notably although not exclusively c-Src, are frequently overexpressed and/or aberrantly activated in a variety of epithelial and non-epithelial cancers. Activation is very common in colorectal and breast cancers, and somewhat less frequent in melanomas, ovarian cancer, gastric cancer, head and neck cancers, pancreatic cancer, lung cancer, brain cancers, and blood cancers. Further, the extent of increased Src family activity often correlates with malignant potential and patient survival. Activation of Src family kinases in human cancers may occur through a variety of mechanisms and is frequently a critical event in tumor progression. Exactly how Src family kinases contribute to individual tumors remains to be defined completely, however they appear to be important for multiple aspects of tumor progression, including proliferation, disruption of cell/cell contacts, migration, invasiveness, resistance to apoptosis, and angiogenesis. This review details the evidence for Src family activation in human tumors, and emphasizes possible consequences to tumor progression. Given the ability of Src and its family members to participate in so many aspects of tumor progression and metastasis, Src family kinases are attractive targets for future anti-cancer therapeutics.
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PMID:Src family kinases in tumor progression and metastasis. 1288 10

Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR that had been produced by coexpression with a kinase in bacteria. We then used GH-induced, phosphorylated GH receptor, purified from overexpressing mammalian cells, in a Far Western-based approach to test whether these seven PTPs were also capable of recognizing ligand-induced, physiologically phosphorylated GHR. In this assay, only TC-PTP, PTP1B, PTP-H1, and SAP-1 interacted with the mature form of the phosphorylated GHR. In parallel, we show that these PTPs recognize very different subsets of the seven GHR tyrosines that are potentially phosphorylated. Finally, mRNA tissue distribution of these PTPs by RT-PCR analysis and coexpression of the wild-type PTPs to test their ability to dephosphorylate ligand-activated GHR suggest PTP-H1 and PTP1B as potential candidates involved in GHR signaling.
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PMID:Identification of protein tyrosine phosphatases with specificity for the ligand-activated growth hormone receptor. 1290 55

Helicobacter pylori is the causative agent of a variety of gastric diseases, but the clinical relevance of bacterial virulence factors is still controversial. Virulent strains carrying the cag pathogenicity island (cagPAI) are thought to be key players in disease development. Here, we have compared cagPAI-dependent in vitro responses in H. pylori isolates obtained from 75 patients with gastritis, peptic ulcer, and gastric cancer (n = 25 in each group). AGS gastric epithelial cells were infected with each strain and assayed for (i) CagA expression, (ii) translocation and tyrosine phosphorylation of CagA, (iii) c-Src inactivation, (iv) cortactin dephosphorylation, (v) induction of actin cytoskeletal rearrangements associated with cell elongation, (vi) induction of cellular motility, and (vii) secretion of interleukin-8. Interestingly, we found high but similar prevalences of all of these cagPAI-dependent host cell responses (ranging from 56 to 80%) among the various groups of patients. This study revealed CagA proteins with unique features, CagA subspecies of various sizes, and new functional properties for the phenotypic outcomes. We further showed that induction of AGS cell motility and elongation are two independent processes. Our data corroborate epidemiological studies, which indicate a significant association of cagPAI presence and functionality with histopathological findings in gastritis, peptic ulcer, and gastric cancer patients, thus emphasizing the importance of the cagPAI for the pathogenicity of H. pylori. Nevertheless, we found no significant association of the specific H. pylori-induced responses with any particular patient group. This may indicate that the determination of disease development is highly complex and involves multiple bacterial and/or host factors.
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PMID:Functional analysis of the cag pathogenicity island in Helicobacter pylori isolates from patients with gastritis, peptic ulcer, and gastric cancer. 1474 52

Carcinoma of the stomach is one of the most prevalent cancer types in the world today. Only a limited number of biomarkers are available for detection and prognostic evaluation of gastric cancer. New advances in identifying molecular biomarkers are essential. Two major forms of gastric cancer are distinguished according to their morphological and clinicopathological classifications (well-differentiated/intestinal type and poorly differentiated/diffuse type)--characteristics that can also be attributed to different oncogene activations. Many genes related to cell cycle regulation and signal transduction have been implicated in gastric cancer progression. In particular, there is convincing evidence that protein tyrosine kinases (PTKs) are involved in oncogenesis and disease progression. To learn more about the biological significance of all expressed PTKs in human cancers, an improved and more-comprehensive PTK profiling approach has been developed to discover additional PTKs activated in cancer cells. With the completion of the human genome project and the availability of cDNA microarrays or DNA chips, the entire human transcriptome can be used for elucidating genes responsible for human gastric cancer oncogenesis and progression.
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PMID:Gastric cancer: prognostic and diagnostic advances. 1498 90


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