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 are many avenues where molecular biology is important in studying the gut, and here we explore methods for defining expression of a new gene family in the gut. We have defined the pattern of trefoil peptide gene expression in the ulceration-associated cell lineage (UACL) and in the nearby mucosa in Crohn's disease. In the UACL, human spasmolytic polypeptide mRNA and peptide are expressed in the acinar and proximal duct cells, whereas pS2 mRNA and peptide are found in the distal duct cells and in the surface cells. In adjacent mucosa, pS2 mRNA and protein are expressed ectopically by goblet cells. Ultrastructural immunolocalisation showed the pS2 to be co-packaged in the mucous cell granules. pS2 peptide was demonstrated in local neuroendocrine cells and was also co-packaged with the neuroendocrine granules. The crypts associated with the UACL also showed marked neuroendocrine cell hyperplasia. We have also cloned the newest trefoil peptide intestinal trefoil factor from human and rat intestinal mucosa and shown its co-expression with mucus by normal intestinal goblet cells. The co-packaging of the same secretory protein in both mucous and neuroendocrine granules, which have different functions, is unusual and indicates an important role for pS2 in the secretory process itself or as a ligand delivered to its receptor via multiple routes. We conclude that the trefoil peptides are widely distributed in the intestine in inflammatory bowel disease and are of considerable potential functional importance.
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PMID:Trefoil peptide expression in intestinal adaptation and renewal. 143 65

We have examined the proliferative organization of the ulcer-associated cell lineage (UACL), in a series of human ileal tissues involved by Crohn's disease, using antibodies to trefoil peptides and Ki-67. The UACL arises in conjunction with endodermal damage and is likely to play a role in subsequent tissue repair. Our study supports the view that the UACL initially forms through extrusion from the base of a parent intestinal crypt without indigenous mitotic activity. Eventually a duct forms extending to the gut surface and within this duct a proliferative zone develops. We also confirm that the trefoil peptides pS2 and hSP, which play a major role in the repair process, are spatially segregated within the UACL with a zone of overlap in the duct. Using triple antibody labelling techniques we have demonstrated that the zone of overlap of these peptides coincides with the proliferative region and provides evidence for a novel stem cell zone.
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PMID:The kinetic organization of the ulcer-associated cell lineage (UACL): delineation of a novel putative stem-cell region. 755 Jun 7

The distribution of the two trefoil peptides pS2 and human spasmolytic polypeptide (hSP) and their mRNAs was investigated in 90 selected oesophageal biopsies, 23 of which contained epithelium with wholly gastric cardiac-type morphology, 52 specialized (intestinal)-type metaplasia, and 15 non-metaplastic oesophageal epithelium. No fundic-type epithelium was represented. The cardiac-type epithelium resembled true gastric antral epithelium, with hSP and pS2 mRNA localization to the superficial/foveolar compartment and hSP mRNA alone in deeper glands. The pattern of peptide distribution was broadly in line with the mRNA, but hSP peptide was generally not demonstrable in the surface epithelium. pS2 immunostaining was diffusely cytoplasmic, whereas in specialized-type mucosa it was aggregated and cytoplasmic. hSP mRNA was demonstrable in surface epithelium of incomplete- but not complete-type intestinal (specialized) metaplasia. Deep glands with morphological features of pyloric glands/ulcer-associated cell lineage (UACL) typically contained only hSP peptide and its mRNA. In three biopsies containing specialized epithelium, small foci morphologically identical to true small intestinal surface epithelium were seen in which only pS2 mRNA and peptide were found and then only in rare goblet cells. Neither squamous epithelium nor oesophageal glands contained demonstrable pS2/hSP mRNA or peptide. The function of these proteins in the metaplastic mucosa of Barrett's oesophagus is unknown but they may reflect an epithelium responding to repeated insult. Their localization facilitates definition of the disparate epithelium types seen in this portion of the gut, with both native gastric and intestinal epithelia, and may help to pinpoint high-risk epithelium in Barrett's oesophagus, a potentially preneoplastic condition.
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PMID:Expression of the trefoil peptides pS2 and human spasmolytic polypeptide (hSP) in Barrett's metaplasia and the native oesophageal epithelium: delineation of epithelial phenotype. 793 41

Porcine pancreatic spasmolytic polypeptide (PSP) belongs to a large family of homologous growth factor-like polypeptides characterized by a disulfide-linked "trefoil motif," duplicated and conserved in various family members. PSP contains two trefoil motifs, has several pharmacological actions on the gut, and has growth factor properties on epithelial cells in vitro. The human PSP analogue, human spasmolytic polypeptide, appears to be involved in many regenerative situations and, especially, in healing gastrointestinal ulcers. One member of the trefoil family, pS2, is secreted in approximately 50% of estrogen-dependent human breast carcinomas, which has led to its use as a tumor prognostic marker. Both pS2 and human spasmolytic polypeptide are also widely expressed in chronic gastrointestinal ulcerative conditions such as Crohn disease. Here we report the three-dimensional structure at 2.6-A resolution of a trefoil-containing protein, namely PSP, purified from porcine pancreas. The structure shows two homologous domains that share a supersecondary structure and disulfide bond pattern. The two domains pack asymmetrically giving rise to a number of protruding loops, exposed clefts, and an unusual electrostatic surface potential. Knowledge of the structure of PSP should allow the design of mutants to investigate further the function of PSP and other trefoil-containing peptides.
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PMID:Crystal structure of a disulfide-linked "trefoil" motif found in a large family of putative growth factors. 830 36

Members of the trefoil family of peptides are generally small stable secreted molecules, structurally related by the presence of one, or up to six, compact 6-cysteine motifs. Several trefoil peptides are expressed in mammalian gut and Xenopus gut and skin, often in association with mucins. Chronic ulcerative conditions of the gut, such as Crohn's disease, result in the growth of glandular structures of the ulcer-associated cell lineage (UACL) that secrete epidermal growth factor/urogastrone, transforming growth factor-alpha, and at least three trefoil peptides [pS2, human spasmolytic polypeptide (hSP), and intestinal trefoil factor (hITF/hP1.B)]. Neuroendocrine and goblet cells near the UACL are "recruited" into expressing pS2 and hSP, but the purpose of this concerted expression is unclear. A role in mucosal healing has been proposed. Biological functions of trefoil peptides have been difficult to establish. Pancreatic spasmolytic polypeptide of porcine origin inhibits gastric acid secretion and smooth muscle contraction and is a growth factor for some cultured cells, but pS2, once thought to be breast cancer specific, is not a mitogen. Recombinant trefoil peptides have allowed localization of binding sites and will allow structure-activity relationships to be studied, once the functions are clear.
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PMID:Trefoil peptides: a newly recognized family of epithelial mucin-associated molecules. 836 6

There is a growing body of evidence supporting the hypothesis that members of the trefoil peptide family are involved actively in maintaining the integrity of the gastrointestinal mucosa and facilitating its repair. To date, three trefoil peptides are known in man: pS2, ITF and SP. Each is a secretory peptide expressed in specific compartments throughout the gut, in patterns that appear generally to be conserved between mammalian species. Ulceration, whether due to common pathological processes or experimentally induced, results in altered local expression of trefoil peptides. In diverse chronic ulcerative conditions in man, glandular structures develop within the mucosa, derived from the UACL. These UACL glands express three trefoil peptides, EGF and lysozyme, all potentially able to contribute to the healing process. In fact local goblet and endocrine cell types may also be recruited to secrete pS2 into the local environment. In experimental ulcers, in rate stomach or intestinal resection margins, there is also accentuation of trefoil peptide expression at the margins and in the poorly differentiated mucous cells extending out presumably in attempts to restore epithelial integrity. Several trefoil peptides have been expressed as 'recombinant' proteins in bacterial, baculoviral or yeast systems, and these procedures have allowed some of the biological properties of these peptides to be determined. In vitro, rITF, hITF and hSP are motogens, able to promote migration of epithelial cells. In vivo, rITF and hSP are able to prevent much of the gastric damage effect by a single dose of indomethacin, when given systemically. There is synergy between EGF and rITF both in vitro and in vivo, which may allow the development of new peptide therapies for ulceration that will maximize repair and minimize cell proliferation.
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PMID:Trefoil peptides. 873 4

Human pS2 (trefoil factor family 1, TFF1), a 60-amino acid member of the trefoil peptide family, forms dimers via Cys58 and may stimulate gut repair. The effects of dimeric pS2-TFF1 and monomeric pS2-TFF1 (Cys58 replaced by Ser58) were compared in models of wound healing. Rats given dimeric pS2-TFF1 at 25 and 50 micrograms/kg per h had 50 per cent and 70 per cent reduction in gastric damage induced respectively by indomethacin (20 mg/kg subcutaneously) and restraint (P < 0.01). Monomeric pS2-TFF1, at the same doses, was significantly less effective at reducing injury (about half the amount of protection, P < 0.01 vs. same doses of dimeric). The rate of migration of cells at the leading edge of wounded monolayers of the human colonic cell line HT29 was increased by addition of dimeric or monomeric forms of pS2-TFF1 (0.65-325 micrograms/ml). Dimeric pS2-TFF1 had a greater effect than the monomeric form at all doses tested (P < 0.05). Cell migration induced by pS2-TFF1 was blocked by a pS2-TFF1 antibody, but not by a transforming growth factor beta neutralizing antibody. pS2-TFF1 did not influence cell proliferation as assessed by thymidine incorporation. The increased biological effects of dimeric pS2-TFF1 might be due to direct interaction of Cys58 with a putative trefoil receptor or, more likely, dimerization of pS2-TFF1 might stabilize the interaction with its receptor. This may involve a bivalent interaction of residues on the surfaces of the two trefoil domains.
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PMID:Dimerization of human pS2 (TFF1) plays a key role in its protective/healing effects. 971 41

This paper reviews areas of interest in gut mucosal growth factor physiology. Several epidermal growth factor (EGF)-like peptides (EGF, transforming growth factor [TGF]-alpha, heparin-binding EGF-like peptide, amphiregulin, and betacellulin) have been identified in the gut, EGF is produced by the salivary glands and is present in milk. It may act on the mucosa from the lumen as a surveillance peptide promoting mucosal repair. A stem-cell-derived "ulcer-associated cell lineage" develops adjacent to ulcers and produces EGF, which may play a role in ulcer healing. TGF-alpha is expressed by villus enterocytes and may have an important role in mucosal healing. The Trefoil peptides (pS2, spasmolytic polypeptide, intestinal trefoil factor) are protease resistant molecules secreted by mucin cells throughout the gut, with a role in mucosal healing. The TGF-beta family inhibit cell proliferation, and promote cell differentiation. TGF-beta has a gradient of expression along the crypt villus axis, with maximum production at the villus tip. It is suspected that it may prevent cell proliferation and support differentiation of villus enterocytes. Hepatocyte growth factor is a multifunctional growth factor expressed in many tissues, including the gastrointestinal tract. It has a role in organogenesis. Intestinal adaptation is highly dependent on enteral nutrition, and it is likely that growth factors are involved in adaptation. Little is known, however, about interactions between nutrients and growth factors. Milk contains a range of potentially important growth factors. Their biological significance is uncertain, and this is an area of active research.
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PMID:Growth factors and the gastrointestinal tract. 978 59

The gastrointestinal tract is exposed to environmental insult as a result of food intake or in pathological conditions such as diarrhoea, and is therefore protected by the mucus layer. As part of it, trefoil peptides (TFFs) are able to modify the visco-elastic properties of the mucus, protect against experimental ulceration, and promote repair of the epithelia. We investigated, using transient reporter gene assays and RT-PCR in the gastric carcinoma cell line MKN45 and colon carcinoma cell lines LS174T and HT29, whether ethanol and osmotic changes can modify transcriptional activity of TFFs. In a mild hypotonic environment (200 mosmol/l) all three TFF genes were up-regulated by at least a factor of 2. In hypertonic medium (400 mosmol/ll), TFF1 and TFF3 were down-regulated, whereas TFF2 was up-regulated by elevated concentrations of sodium or chloride in MKN45. Raising the osmolality by ethanol resulted in an up-regulation of TFF3 in both colon cell lines but not in the gastric cell line. We conclude that alteration in TFF gene expression is a response of gut epithelia to deal with osmotic forces and ethanol.
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PMID:Osmotic changes and ethanol modify TFF gene expression in gastrointestinal cell lines. 984 2

The winged helix transcription factors HNF-3/FKH (forkhead homologs) activate endodermal-derived and acute-phase gene expression and control gut development in Drosophila. Trefoil factor family (TFFs) peptides are vertebrate products secreted by mucin-producing epithelial cells of the gastrointestinal tract involved in restitution and repair of the mucosa. They are positively regulated in ulcerative and neoplastic conditions. We describe a consensus sequence in human and rodent TFF promoters close to the TATAA box showing striking similarity to the binding site of the HNF-3/FKH family. In gel retardation assays, HNF-3 alpha and beta bound predominantly to the site in TFF1 (formerly pS2) and, to a lesser extent, to the sites in TFF2 or TFF3. Mutations generated in this motif severely impaired transcription of TFF1 reporter genes. Cotransfection with expression vectors of HNF-3alpha and beta, but not the related HFH 11A and B, specifically activated the wild-type TFF1 reporter genes. Activation of endogenous expression of TFF1 by HNF-3 alpha and beta gene products was more than 1000 fold in the pancreatic cell line Capan-2 and fivefold in the gastric cell line MKN-45, whereas the intestinal cell lines HUTU 80 and HT-29 displayed no effect. Thus, HNF-3/FKH factors contribute causally to cell-specific regulation of TFF genes and may explain the acute-phase response of TFF peptides.
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PMID:Hepatocyte nuclear factor 3 (winged helix domain) activates trefoil factor gene TFF1 through a binding motif adjacent to the TATAA box. 1007 75


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