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D Taupin

Publications and source records attributed to D Taupin.

8 recordsLinked to original sources
PubMed2001

Augmented intestinal trefoil factor (TFF3) and loss of pS2 (TFF1) expression precedes metaplastic differentiation of gastric epithelium.

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.

Adenocarcinoma↗
PubMed2001

Towards a molecular approach to gastric cancer management.

Gastric cancer is a leading cause of cancer death worldwide. Most patients with gastric cancer present with locally advanced and incurable disease, and overall survival is poor. Considerable research efforts towards the epidemiology and pathogenesis of gastric cancer have not been translated into treatment success. We discuss current concepts of the pathogenesis of gastric cancer and how recent research advances, in particular global gene expression strategies, may improve this understanding, and suggest a framework wherein these approaches may be used.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Mitogen-activated protein kinase activation regulates intestinal epithelial differentiation.

BACKGROUND & AIMS: The human colon cancer-derived cell line HT29 displays a multipotent phenotype. A subclone of HT29 cells containing numerous mucous granules and termed HT29-18-N2 was studied to determine the cellular mechanisms underlying a switch to the differentiated phenotype. METHODS: Northern (RNA) blotting, immunoblotting, and immunocytochemistry of HT29-N2 cells, grown under glucose-containing and glucose-free conditions with or without the use of the mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor PD98059, were performed. RESULTS: Loss of activation of the MAP kinases ERK 1 and ERK 2 in HT29-N2 cells upon a change to glucose-free growth medium preceded the change in phenotype and up-regulation of the goblet cell gene product intestinal trefoil factor (ITF). Long-term pharmacological MAP kinase inhibition with the MEK inhibitor PD98059 induced expression of the terminal differentiation markers ITF, sucrase-isomaltase, and the mucin gene MUC2. This was accompanied by morphological evidence of gland formation and mucin secretion and the appearance of discrete goblet cell and enterocyte populations. Induction of ITF and sucrase-isomaltase after MEK inhibition in HT29-N2 cells did not involve loss of MAP kinase responsiveness and was not mediated by receptor tyrosine kinases. CONCLUSIONS: Regulation of ERK activation may be a key biochemical switch responsible for terminal differentiation of components of the crypt-villus unit.

Antigens, Differentiation↗
PubMed1999

The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation.

The trefoil gene family of mucus cell-secreted proteins is a critical mediator of gastrointestinal mucosal restitution. Transcription of trefoil genes is induced during mucosal repair, but the regulatory mechanisms involved are unknown. Mice deficient in the intestine-specific peptide intestinal trefoil factor (ITF), in which colonic restitution is lethally impaired, showed reduced expression of the gastric trefoil genes SP and pS2, suggesting that trefoil peptides may individually regulate transcription of the entire family. In gastric cell lines, the trefoils were shown to act in a manner suggestive of immediate-early genes capable of auto- and cross-induction through cis-acting regulatory regions. Trefoil-mediated transcriptional regulation required activation of the Ras/MEK/MAP kinase signal transduction pathway. EGF receptor (EGF-R) activation was also necessary for trefoil auto- and cross-induction, and both spasmolytic polypeptide (SP) and ITF stimulation of gastric cell lines led to phosphorylation of EGF-R. Nevertheless, ITF and ITF-thioredoxin cell surface binding at 4 degrees C colocalized not with EGF-R, but with CD71, which is found in clathrin-coated pits, suggesting that integration of trefoil peptide responses may occur after internalization. As EGF-R expression is itself strongly induced after mucosal damage, the trefoil/EGF-R relationship may be pivotal in the generation and maintenance of the mucosal repair phenotype.

Animals↗
PubMed1996

Conserved expression of intestinal trefoil factor in the human colonic adenoma-carcinoma sequence.

Human intestinal trefoil factor (ITF), a mucosa-associated trefoil peptide, has been implicated in maintenance of mucosal integrity and may denote commitment to goblet cell differentiation. We have quantitated and localized ITF expression in normal and neoplastic colons, determined the molecular forms present, and examined the relationships among ITF expression and mucin production and increasing dysplasia. Normal and neoplastic human colonic mucosa (n = 30) were extracted for quantitation by ITF radioimmunoassay and size determination by gel filtration and immunoblotting. Paraffin sections of normal bowel, hyperplastic polyps, adenomatous polyps, and adenocarcinoma were examined for ITF immunohistochemistry and mucin histochemistry. The predominant molecular species in both normal and neoplastic colon was a 7-kd monomer. Staining was localized to goblet and Paneth cells and the luminal surface in normal colon and in most adenomatous polyps but not hyperplastic polyps; this colocalized with periodic acid-Schiff histochemistry. ITF staining of undifferentiated cells was seen with increasing dysplasia, and Golgi region immunoreactivity was highly conserved in adenocarcinoma, independent of the presence of periodic acid-Schiff-positive mucin. ITF concentration in colonic extracts was 10 to 200 pmol/g. Levels in normal (88.1 +/- 15.1 pmol/g) and malignant (90.1 +/- 12.7 pmol/g) tissue were comparable. In carcinomas, there were significant associations among ITF expression and degree of differentiation and mucin presence. Loss of expression was associated with tumor necrosis and advanced Duke's stage. ITF is uniformly processed in normal and neoplastic colons. Goblet cell-derived ITF is associated with stainable mucin production. ITF synthesis by non-goblet colonocytes, however, is highly conserved in neoplastic differentiation.

Adenoma↗
PubMed1993

Mammalian bombesin as a hormone in ovine pregnancy: ontogeny, origin, and molecular forms.

Mammalian gastrin-releasing peptides (GRP) are present in female reproductive tissues and stimulate uterine contraction and DNA synthesis in the endometrium. We set out to establish whether the GRP were likely to play a role in fetal development by measuring the fetal and maternal plasma concentrations in chronically cannulated fetal sheep from 115 days gestation to term (145 days) and for 18 days after parturition. Placental fluids and fetal urine were also obtained. In a separate series of animals, uterine, placental, and fetal gut and lung tissues were collected. Samples were extracted in acid and assayed by radioimmunoassay, and molecular forms were characterized by high-performance liquid chromatography. GRP were present in the decidua (> 10 pmol/g), as well as placental, uterine, lung, and gastrointestinal tissues (all < 6 pmol/g). Fetal and maternal plasma GRP were elevated compared with nonpregnant ewes, falling sharply after parturition. Placental fluids and urine also contained GRP (80-410 fmol/ml). The main molecular form in all tissues and fluids examined coeluted with porcine GRP-(18-27). GRP immunoreactivity was primarily localized to epithelial cells of the decidua. These data suggest that plasma GRP is probably derived from the decidua and may play a role as a circulating hormone in ovine fetal and uterine development.

Animals↗