Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is considerable debate about whether the mucous neck cell (MNC) in the mucosa of the gastric corpus is merely a transit cell population, intermediate between gastric stem cells and the differentiated zymogenic (chief or peptic) cell lineages, or has distinct functions of its own. To cast light on these possibilities, the secretory phenotype of the MNC has been examined. Archival gastric body samples from non-ulcer dyspepsia biopsies and gastrectomies performed for peptic ulcer disease were stained with antibodies to the trefoil peptides TFF1/pS2 and TFF2/SP, pancreatic secretory trypsin inhibitor (PSTI), epidermal growth factor (EGF) and its receptor (EGFR), and to the MUC1 gene product--HMFG2. Human MNCs express PSTI, TFF1/pS2, TFF2/SP, and EGF proteins, while rat MNCs express TFF2/SP; the mucin contained in the MNCs is diastase/periodic acid Schiff (D/PAS)-positive and stains with human milk fat globulin (HMFG2). The canaliculi but not the cytoplasm of adjacent parietal cells were also decorated focally by D/PAS, by HMFG2, and by antibodies to TFF2/SP and TFF1/pS2. These findings favour the hypothesis that MNCs have a defined phenotype and are thus a separate and distinct cell lineage, secreting a number of luminally-active peptides which protect the gastric mucosa, and in particular the adjacent parietal cells, from the effects of secreted gastric acid. Moreover, a considerable degree of similarity in secretory profile is noted between MNCs and the so-called 'reparative lineages' in the gut--the ulcer-associated cell lineage (UACL) and hyperplastic polyp epithelium. If, on the other hand, the MNCs are indeed a transit population differentiating into zymogenic or peptic cells, then it is clear that having differentiated into one secretory phenotype producing a range of peptides, the MNC then proceeds to differentiate into a cell with a totally different secretory phenotype, a phenomenon unique in gastrointestinal cell lineage relationships.
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PMID:The mucous neck cell in the human gastric corpus: a distinctive, functional cell lineage. 1039 88

One of the early events in inflammation and epithelial restitution of the gastrointestinal tract is the up-regulation of secretory peptides belonging to the trefoil factor family (TFF) that promote cell migration, protect and heal the mucosa. Their major expression site is stomach (TFF1, TFF2) and intestine (TFF3). Located in the 5'-flanking region of the genes are several consensus sites for members of the GATA transcription factors known to control gut-specific gene expression. By reverse transcription-PCR (RT-PCR), GATA-6 was shown to be expressed in a variety of tumor cell lines of gastric, intestinal and pancreatic origin. In MKN45, KATOIII and LS174T, cotransfection with TFF reporter genes and GATA-6 expression vectors revealed that GATA-6 activates TFF1 and TFF2 4-6-fold, without an effect on TFF3. The functional contribution of GATA binding sequences in the reverse orientation was further characterized by reporter gene assays using TFF2 deletion constructs and by gel shift experiments.
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PMID:Transcription factor GATA-6 activates expression of gastroprotective trefoil genes TFF1 and TFF2. 1068 77

The trefoil peptides spasmolytic polypeptide (SP), intestinal trefoil factor (ITF), and pS2 show lineage-specific expression in the normal gut and are strongly induced after mucosal injury. We assessed the relationship between this induction and the development of the regenerative epithelial lineage over time in the rat stomach and verified these observations in the metaplastic and dysplastic human stomach. Antral or colonic ulcers were induced in Wistar rats by application of serosal acetic acid and tissues harvested 2 hours to 125 days later. Human endoscopic biopsies or gastric resection specimens were also assessed. Tissues were examined by radioimmunoassay, immunoblotting, or immunohistochemistry for ITF, SP, and transforming growth factor alpha (rat) or ITF and pS2 (human) expression. ITF and SP mRNA in antral ulcer margins was localized by in situ hybridization. ITF and SP peptide expression rose steadily in ulcer margins after 4 days, with the rise in ITF being more pronounced. By 40 days, several hundred-fold elevations in ITF levels were present, with a field effect in uninvolved mucosa. Hyperproliferative, elongated glands of undifferentiated cells expressing abundant trefoil peptides and acid sulfomucins were present after day 12 and persisted after ulcer healing. ITF mRNA was aberrantly expressed in basal and mid-regions of these regenerative glands. In contrast, transforming growth factor alpha peptide expression rose promptly after injury then fell to baseline levels with healing. Seven months after injury, gastric atrophy, intestinal metaplasia, and severe dysplasia with conserved ITF expression were seen. ITF was also induced in human intestinal metaplasia and conserved in all gastric cancers, whereas expression of the gastric peptide pS2 was progressively reduced in the progression from metaplasia to dysplasia. Persistent, selective overexpression of ITF, possibly acting in an autocrine fashion, is a feature of regeneration after antral ulceration, and may provide insight into the nature of metaplastic phenotypes arising from chronic gastric injury. The loss of pS2 expression in metaplasia and cancer supports a role for this protein in gastric tumor suppression.
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PMID:Augmented intestinal trefoil factor (TFF3) and loss of pS2 (TFF1) expression precedes metaplastic differentiation of gastric epithelium. 1131 Aug 32

The estrogenic soy isoflavone, genistein, stimulates growth of estrogen-dependent human breast cancer (MCF-7) cells in vivo. Genistin is the glycoside form of genistein and the predominant form found in plants. It is generally believed that genistin is metabolized to the aglycone genistein in the lower gut. However, it is unclear if the rate of metabolism of genistin to genistein is sufficient to produce a level of genistein capable of stimulating estrogen-dependent breast cancer cell growth. Our hypothesis was that dietary genistin would stimulate tumor growth similar to that observed with genistein in athymic mice. To test this hypothesis, genistin or genistein was fed to athymic mice containing xenografted estrogen-dependent breast tumors (MCF-7). Mice were fed either genistein at 750 p.p.m. (parts per milllion) or genistin at 1200 p.p.m., which provides equal molar concentrations of aglycone equivalents in both diets. Tumor size was measured weekly for 11 weeks. At completion of the study, half of the animals per treatment group were killed and tumors collected for evaluation of cellular proliferation and estrogen-responsive pS2 gene expression. Incorporation of bromo-deoxyuridine into cellular DNA was utilized as an indicator of cellular proliferation. Dietary genistin resulted in increased tumor growth, pS2 expression and cellular proliferation similar to that observed with genistein. The remaining mice were switched to diets free of genistin and genistein. When mice were placed on isoflavone free diets, tumors regressed over a span of 9 weeks. Next, we examined how effectively and where metabolism of genistin to genistein occurred in the digestive tract. We present evidence that demonstrates conversion of genistin to its aglycone form genistein begins in the mouth and then continues in the small intestine. Both human saliva and the intestinal cell-free extract from mice converted genistin to genistein. In summary, the glycoside genistin, like the aglycone genistein, can stimulate estrogen-dependent breast cancer cell growth in vivo. Removal of genistin or genistein from the diet caused tumors to regress.
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PMID:Dietary genistin stimulates growth of estrogen-dependent breast cancer tumors similar to that observed with genistein. 1157 7

The trefoil factor family peptides TFF1, TFF2, and TFF3 are important for gut mucosal protection and restitution. Keratinocyte growth factor (KGF) stimulates proliferation and differentiation of epithelial cells with potent effects on goblet cells. To investigate interactions between food intake and KGF, rats were fed ad libitum (control), fasted for 72 h, or fasted for 72 h and then refed for 72 h with or without KGF (3 mg. kg(-1). day(-1)). With fasting, goblet cell number in duodenum increased, TFF3 mRNA in duodenum and jejunum decreased, and TFF3 protein did not change or increased. KGF during fasting stimulated colonic growth, normalized TFF3 mRNA in duodenum and jejunum, and broadly upregulated gut goblet cell number and TFF3 protein expression. With fasting-refeeding, KGF increased small bowel and colonic mucosal growth, goblet cell number, and TFF3 protein but had variable effects on TFF3 mRNA. KGF induced TFF2 mRNA and protein in duodenum and jejunum with both nutritional regimens. We conclude that nutrient availability modifies rat intestinal goblet cell number, TFF3 mRNA, and the gut-trophic effects of KGF in a region-specific manner. KGF enhances TFF2 expression in proximal small bowel and increases goblet cell number and TFF3 protein content throughout the intestine independent of food intake.
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PMID:Trefoil peptide expression and goblet cell number in rat intestine: effects of KGF and fasting-refeeding. 1238 39

Necrotising enterocolitis (NEC) remains an overwhelming gastrointestinal (GI) emergency in premature infants, with an annual incidence of 350 cases and a mortality of 23% in the United Kingdom. The aetiology of NEC is multifactorial and its pathogenesis poorly understood. It is characterised by severe necrotic damage to the intestine. Mucus is an adherent, viscoelastic gel layer protecting the delicate underlying epithelium from lumenal aggressors such as digestive enzymes and bacterial toxins. The group of trefoil factor peptides (TFF1-3) are part of the protective mechanism operating in the intestinal mucosa and play a fundamental role in epithelial protection, repair, and restitution. These secreted peptides have been identified in a site-specific pattern in the GI mucosa, and their expression has been shown to be upregulated in early stages of mucosal repair. The role of trefoil peptides in neonatal mucosal protection has not been well investigated. Impaired mucosal regeneration due in part to failure of upregulation of TFF expression may contribute to the pathogenesis of NEC. The aim of this study was to investigate TFF1-3 mRNA expression and to identify the gene product in the GI tracts of normal neonatal controls and infants with NEC. Parents of all babies having a laparotomy in the neonatal period (defined as up to 44 weeks' gestation) and bowel resection were approached for written consent. Bowel samples were fixed in formalin and then embedded in paraffin in an RNAse-free manner. In situ hybridisation and immunohistochemistry were performed to examine the pattern of trefoil mRNA expression and to localise the peptides in the neonatal GI tract. Forty neonatal bowel specimens were examined. Twelve patients had NEC, eight were recovering from NEC, and 20 control specimens were obtained. TFF1 and TFF2 mRNA expression were not detected in the majority of NEC specimens, and there was a relative downregulation of TFF3 expression in 83% of NEC patients. TFF1 and TFF2 expression were noted in the recovery phase from NEC. Immunohistochemistry revealed a decrease in TFF3 gene product in sites adjacent to mucosal damage secondary to NEC. In acute NEC there was no apparent expression of TFF1 and 2 protein. In the group of patients recovering from NEC, TFF1 and 2 expression were seen in association with regenerative changes in the mucosa. Previous data has shown TFF1-3 to be upregulated in the acute phase response to mucosal injury in the gut. Trefoil peptides have been shown to promote epithelial cell migration and protect against apoptosis. Our results suggest that there is a lack of TFF expression in response to NEC in the premature gut. This may lead to impaired restitution of the mucosa and contribute to the cascade of bowel necrosis and generalised sepsis characteristic of NEC.
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PMID:Impaired mucosal regeneration in neonatal necrotising enterocolitis. 1557 91

Invasive pancreatic cancer is thought to develop through a series of noninvasive duct lesions known as pancreatic intraepithelial neoplasia (PanIN). We used cDNA microarrays interrogating 15,000 transcripts to identify 49 genes that were differentially expressed in microdissected early PanIN lesions (PanIN-1B/2) compared with microdissected normal duct epithelium. In this analysis, a cluster of extrapancreatic foregut markers, including pepsinogen C, MUC6, KLF4, and TFF1, was found to be up-regulated in PanIN. Up-regulation of these genes was further validated using combinations of real-time reverse transcription-PCR, in situ hybridization, and immunohistochemistry in a total of 150 early PanIN lesions from 81 patients. Identification of these gastrointestinal transcripts in human PanIN prompted assessment of other foregut markers by both semiquantitative and real-time reverse transcription-PCR, revealing similar up-regulation of Sox-2, Gastrin, HoxA5, GATA4/5/6, Villin and Forkhead 6 (Foxl1). In contrast to frequent expression of multiple gastric epithelial markers, the intestinal markers intestinal fatty acid binding protein, CDX1 and CDX2 were rarely expressed either in PanIN lesions or in invasive pancreatic cancer. Hedgehog pathway activation induced by transfection of immortalized human pancreatic ductal epithelial cells with Gli1 resulted in up-regulation of the majority of foregut markers seen in early PanIN lesions. These data show frequent up-regulation of foregut markers in early PanIN lesions and suggest that PanIN development may involve Hedgehog-mediated conversion to a gastric epithelial differentiation program.
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PMID:Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. 1575 53

Abnormalities in the expression of DMBT1 (deleted in malignant brain tumors 1) have been implicated in the development of esophageal, gastric and colorectal cancers of the alimentary tract, but the underlying mechanism remains unclear. In the present study, using the gastric cell line AGS, we identified two intracellular signaling molecules protein kinase C (PKC) and extracellular signal-related kinase (ERK). They mediated both the phorbol myristate acetate (PMA) downregulation of DMBT1 expression and the initiation of cell differentiation, which was measured by cell cycle withdrawal and the induction of the tissue-specific marker trefoil factor 1 (TFF1). A time-course study showed that following the PMA activation of ERK kinase, the induction of TFF1 and the reduction of DMBT1 were detected at the same time point. We then demonstrated a minimal level of DMBT1 in proliferating AGS cells seeded at low density, where ERK activity was high. Reduction of ERK activity, either by an ERK inhibitor PD98059 or by high-density seeding, significantly reduced AGS cell growth judged by CFSE labeling. This cellular effect was elicited by cyclin D/p21 (Cip/Waf1) and G(0)/G(1) arrest, and was accompanied by a marked increase in DMBT1-expressing cells. Finally, we showed that siRNA directed against DMBT1 had no effect on the induction of a cell growth arrest marker, gut-enriched Kruppel-like factor (GKLF), but reduced the PMA induction of TFF1. Along with its upregulation coinciding with G(0)/G(1) arrest, and its attenuation in differentiated cells, these results suggest that the transient induction of DMBT1 is apparently specific at an early stage of gastric epithelial differentiation-like process, when it may play a role in cell fate decision. Consistent with such a potential function, we detected frequent abnormalities of the DMBT1 expression in the specimens of human gastric adenocarcinoma.
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PMID:Induction of DMBT1 expression by reduced ERK activity during a gastric mucosa differentiation-like process and its association with human gastric cancer. 1576 Sep 20

Previous studies revealed novel genetic changes in the duodenal mucosa of iron-deprived rats during postnatal development. These observations are now extended to compare the genetic response to iron deficiency in the duodenum versus jejunum of 12-wk-old rats. cRNA samples were prepared from the duodenal and jejunal mucosa of three groups each of control and iron-deficient rats and hybridized with RAE 230A and 230B gene chips (Affymetrix). Stringent data reduction strategies were employed. Results showed that several genes were similarly induced in both gut segments, including DMT1, Dcytb, transferrin receptor 1, heme oxygenase 1, metallothionein, the Menkes copper ATPase (ATP7A), tripartitie motif protein 27, and the sodium-dependent vitamin C transporter. However, a subset of genes showed regulation in only one or the other gut segment. In duodenum only, gastrokine 1, trefoil factor 1 and claudin 2 were induced by iron-deficiency. Other genes previously identified were only regulated in the duodenum. Overall, these studies demonstrate similarities and distinct differences in the genetic response to iron deprivation in the duodenum versus jejunum and provide evidence that more distal gut segments also may play a role in increasing iron absorption in iron-deficiency anemia.
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PMID:Gene chip analyses reveal differential genetic responses to iron deficiency in rat duodenum and jejunum. 1662 62

Cervical remodeling during pregnancy and parturition is a single progressive process that can be loosely divided into four overlapping phases termed softening, ripening, dilation/labor, and post partum repair. Elucidating the molecular mechanisms that facilitate all phases of cervical remodeling is critical for an understanding of parturition and for identifying processes that are misregulated in preterm labor, a significant cause of perinatal morbidity. In the present study, biomechanical measurements indicate that softening was initiated between gestation days 10 and 12 of mouse pregnancy, and in contrast to cervical ripening on day 18, the softened cervix maintains tissue strength. Although preceded by increased collagen solubility, cervical softening is not characterized by significant increases in cell proliferation, tissue hydration or changes in the distribution of inflammatory cells. Gene expression studies reveal a potentially important role of cervical epithelia during softening and ripening in maintenance of an immunomucosal barrier that protects the stromal compartment during matrix remodeling. Expression of two genes involved in repair and protection of the epithelial permeability barrier in the gut (trefoil factor 1) and skin (serine protease inhibitor Kazal type 5) were increased during softening and/or ripening. Another gene whose function remains to be elucidated, purkinje cell protein 4, declines in expression as remodeling progressed. Collectively, these results indicate that cervical softening during pregnancy is a unique phase of the tissue remodeling process characterized by increased collagen solubility, maintenance of tissue strength, and upregulation of genes involved in mucosal protection.
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PMID:Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice. 1766 Feb 42


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