Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SMPI is a proteinaceous microbial metalloproteinase inhibitor that was isolated from Streptomyces nigrescens TK-23 in 1979. SMPI is known to selectively inhibit the metalloproteinases in the gluzincin family, according to the Rawling and Barrett classification. There has been no report on the interaction of a metalloproteinase in the family of gluzincins with its specific proteinaceous inhibitor. We have solved the solution structure of SMPI by NMR. Here, we report the binding mode of SMPI to thermolysin, based on the model complex structure generated using our high-resolution NMR structure of SMPI and the crystal structure of thermolysin. The obtained complex model shows that the extruded loop of SMPI, with the scissile bond Cys64-Val65, is complementary in shape to the active cleft of thermolysin. In the complex, the Cys64 (P1) carbonyl oxygen atom can form a tetrahedral coordination to the active zinc in thermolysin, and simultaneously, the methyl groups of Val65 (P1') are closely located in the hydrophobic S1' pocket in thermolysin. From the electrostatic potential surface calculation, the active loop of SMPI and the active cleft in thermolysin have been shown to be complementary in the surface charge distribution, resulting in the stabilization of the complex. The apparently large active loop is less flexible, but maintains a conformation in the nano- to picosecond time-scale, as elucidated from the 15N spin relaxation analysis. This is a quite different structural feature of SMPI from the flexible binding loop generally found in the serine proteinase inhibitors, such as SSI and eglin c, and can be related to the narrow specificity of SMPI. The present study provides the first insight into the interaction between a proteinaceous inhibitor and a gluzincin metalloproteinase.
J Mol Biol 1998 Sep 18
PMID:Elucidation of the mode of interaction of thermolysin with a proteinaceous metalloproteinase inhibitor, SMPI, based on a model complex structure and a structural dynamics analysis. 973 98

Barrett's metaplasia consists of columnar epithelium that replaces the normal esophageal mucosa in patients with chronic gastroesophageal reflux. Because intestinal-type Barrett's metaplasia is the major risk factor for adenocarcinoma development, understanding the mechanisms that predispose the esophageal mucosa to malignant degeneration is clinically important. Glutathione s-transferase (GST)-pi belongs to a class of protective enzymes whose activity has been shown to be much lower in Barrett's metaplasia than in the normal esophagus, where this form of GST is predominant. In the studies described here, using immunocytochemical analysis, we observed higher levels of cytoplasmic GST-pi protein in normal esophageal mucosa than in Barrett's metaplasia. Using northern blot analysis, we also observed lower GST-pi mRNA levels in Barrett's metaplasia than in normal esophagus or adenocarcinomas from the same patients. Using as model systems three Barrett's adenocarcinoma cell lines and short-term organ culture of freshly resected normal esophagus and Barrett's metaplasia, dose-dependent induction of GST-pi mRNA was observed by using butylated hydroxyanisole and dexamethasone. GST-pi mRNA in Barrett's metaplasia was induced up to 2.5-fold with 60 microM butylated hydroxyanisole and nearly fivefold with 320 nM dexamethasone after 24 h. These studies demonstrate the ability to induce protective GST-pi in Barrett's metaplasia and may suggest a mechanism for future chemoprevention studies in patients with this type of epithelium, which is at high risk for malignant degeneration.
Mol Carcinog 1999 Feb
PMID:Induction of glutathione s-transferase-pi in Barrett's metaplasia and Barrett's adenocarcinoma cell lines. 1007 40

Villin is an actin-binding cytoskeletal protein required for brush-border formation in the normal small intestinal and renal proximal tubule epithelium. Villin is a marker of cell differentiation in small intestinal and renal cell lineages, and recent studies have shown villin to be highly expressed in 100% of intestinal-type Barrett's metaplasias. This epithelium is the single greatest risk factor for developing esophageal adenocarcinoma and arises when the normal esophageal squamous epithelium is replaced by a small intestine-like columnar epithelium after damage by chronic gastroesophageal reflux. In intestinal-type Barrett's metaplasia, the villin protein exhibits a highly characteristic staining pattern in which strong apical, brush-border staining of columnar epithelial cells is observed. In this study, the ability to identify intestinal metaplastic cells by using this distinct villin staining pattern was examined in endoscopic esophageal brushings from patients with confirmed Barrett's metaplasia. Esophageal brushings from 81% (17 of 21) of patients with Barrett's metaplasia demonstrated individual columnar cells with the characteristic villin staining pattern, whereas all normal esophageal squamous cells, blood cells, and gastric columnar cells were negative for villin expression. Northern blot analysis demonstrated villin mRNA expression in Barrett's metaplasia but not in the normal squamous esophagus or gastric mucosa from the same patients. The combined use of villin immunohistochemical analysis and esophageal brush cytology may provide a simple and effective method of detecting intestinal-type Barrett's metaplasia in patients at higher risk for developing this epithelium, such as those experiencing chronic gastroesophageal reflux symptoms.
Mol Carcinog 1999 Feb
PMID:Identification of intestinal-type Barrett's metaplasia by using the intestine-specific protein villin and esophageal brush cytology. 1007 41

The Epstein-Barr virus is an agent that causes African Burkitt's lymphoma, infectious mononucleosis, and Hodgkin's disease. It is also related to nasopharyngeal carcinoma and gastric carcinoma. The aim of this study was to evaluate the prevalence of the Epstein-Barr virus in esophageal cancer. Polymerase chain reaction and in situ hybridization were used to detect the Epstein-Barr virus. We detected 103 Epstein-Barr virus positive cells out of 107 of KYSE 273 cells using first standard-PCR. Epstein-Barr virus DNA could not be detected in 30 of the esophageal squamous cell carcinoma cell lines and 2 of the Barrett's esophageal adenocarcinoma cell lines. Out of 77 esophageal cancer patients, 3 cases were found positive for Epstein-Barr virus DNA using polymerase chain reaction. However, by in situ hybridization we found signals in only 1 of the 3 cases, the signal was located in the infiltrating lymphocytes. The Epstein-Barr virus is rarely associated with esophageal cancer.
Int J Mol Med 2000 Apr
PMID:The Epstein-Barr virus is rarely associated with esophageal cancer. 1071 51

Human interleukin (IL)-5 gene transcription is regulated by several transcription factor binding sites, including CLE 0, GATA, and a region from position -123 to -92 known as response element (RE)-II. By expression cloning, a partial protein was identified that bound to concatamers of RE-II. Recombinant protein derived from this initial complementary DNA (cDNA) encoding the partial protein specifically bound to RE-II-containing oligonucleotides in electromobility shift assays. The complete sequence (3,649 bp) was determined by 5' rapid amplification of cDNA ends and comparisons to existing ESTs, and found to be identical to the 3' half of Wolf-Hirschhorn syndrome candidate 1, (WHSC1; also known as Multiple Myeloma SET domain [MMSET]). The full-length protein contains an SET domain and two plant homeodomain-type zinc fingers. Transcription initiation of RE-II binding protein (RE-IIBP) messenger RNA (mRNA) uniquely occurred within the middle of WHSC1 near a region that exhibits complex mRNA splicing. RE-IIBP reactive polyclonal antisera identified proteins in human T-cell nuclear protein extracts of 62 and 66 kD that were consistent with the length of the longest open reading frame in RE-IIBP. In contrast, WHSC1 is predicted to encode a protein of 136 kD. In activated human Jurkat and murine D10.G4.1 T cells, expression of full-length and truncated forms of RE-IIBP repressed RE-II promoter activity of a 5X-RE-II luciferase reporter construct by as much as 75%. In addition, RE-IIBP expressed in activated D10.G4.1 T cells inhibited endogenous murine IL-5 production. The repressor activity of RE-IIBP is consistent with the presence of an SET domain that is found in other proteins that act as gene silencers.
Am J Respir Cell Mol Biol 2001 Jan
PMID:A unique mRNA initiated within a middle intron of WHSC1/MMSET encodes a DNA binding protein that suppresses human IL-5 transcription. 1115 55

Barrett's adenocarcinoma currently shows the highest increase in the incidence of all malignant tumors. Reliable molecular markers to identify Barrett's patients at risk are still missing. Our own results demonstrate that the expression of CD44v6 correlates with the development of dysplasia in colorectal neoplasms. Therefore, we examined the expression of CD44 variants v5 and v6 in normal esophageal mucosa, non-dysplastic Barrett's mucosa, and Barrett's carcinoma. mRNA from biopsy specimens of patients with Barrett's esophagus (n = 19) or Barrett's carcinoma (n = 15) and patients without esophageal diseases (controls; n = 9) were extracted and used as templates for cDNA synthesis. CD44 variants were detected by RT-PCR with primers hybridizing with CD44 sequences up- and downstream of variable exons. CD44v6 expression was found in 36 of 56 biopsy specimens (64%) of non-dysplastic Barrett's mucosa, in 100% of squamous epithelium, and in none of the gastric mucosa specimens. Eleven of 15 specimens (73%) of Barrett's carcinoma tested positive for v6 expression. The identification of v5 expression did not give additional information. There was no correlation between CD44v5 or -v6 expression and staging or grading of the tumors. Expression of CD44v5 and -v6 seems to be independent of the development of cancer in Barrett's mucosa.
Exp Mol Pathol 2002 Jun
PMID:Expression of CD44v5 and -v6 in Barrett's carcinoma is not increased compared to that in nondysplastic Barrett's mucosa. 1200 84

Photodynamic therapy with the pro-drug 5-aminolaevulinic acid (ALA-PDT) is being used for the treatment of Barrett's oesophagus. We postulated that a first early course of ALA-PDT would increase protoporphyrin IX (PPIX) accumulation and thus the efficacy of a second course of ALA-PDT, by manipulating ferrochelatase (FC) and porphobilinogen deaminase (PBG-d) activity. Human EBV-transformed lymphoblastoid cells were used as a model of human tumour cells for the ability to form haem is present in all cells. After a single course of illumination (633 nm, 100 mW/cm2) the FC activity decreased significantly whereas the PBG-d activity did not change. During continued incubation with ALA following the first illumination, cells accumulated up to four times more PPIX than non-illuminated controls [220% +/- 30% versus (vs) 55% +/- 5%; p<0.001]. Two illuminations resulted in more cell death than one illumination (97% +/- 1% vs 80% +/- 2%; p<0.001). Since a second course of ALA-PDT within 3 hr after the first course resulted in a four fold increase in PPIX accumulation and significantly more cell death, we propose that a two course ALA-PDT scheme might improve the efficacy of this treatment for Barrett's oesophagus.
Cell Mol Biol (Noisy-le-grand) 2002 Dec
PMID:Two course illuminating scheme improves aminolevulinic acid photodynamic therapy in cell cultures. 1269 49

The esophageal epithelium is subject to damage from bile acid reflux that promotes normal tissue injury resulting in the development of Barrett's epithelium. There is a selection pressure for mutating p53 in this preneoplastic epithelium, thus identifying a physiologically relevant model for discovering novel regulators of the p53 pathway. Proteomic technologies were used to identify such p53 regulatory factors by identifying proteins that were overexpressed in Barrett's epithelium. A very abundant polypeptide selectively expressed in Barrett's epithelium was identified as anterior gradient-2. Immunochemical methods confirmed that anterior gradient-2 is universally up-regulated in Barrett's epithelium, relative to normal squamous tissue derived from the same patient. Transfection of the anterior gradient-2 gene into cells enhances colony formation, similar to mutant oncogenic p53 encoded by the HIS175 allele, suggesting that anterior gradient-2 can function as a survival factor. Deletion of the C-terminal 10 amino acids of anterior gradient-2 neutralizes the colony enhancing activity of the gene, suggesting a key role for this domain in enhancing cell survival. Constitutive overexpression of anterior gradient-2 does not alter cell-cycle parameters in unstressed cells, suggesting that this gene is not directly modifying the cell cycle. However, cells overexpressing anterior gradient-2 attenuate p53 phosphorylation at both Ser(15) and Ser(392) and silence p53 transactivation function in ultraviolet (UV)-damaged cells. Deletion of the C-terminal 10 amino acids of anterior gradient-2 permits phosphorylation at Ser(15) in UV-damaged cells, suggesting that the C-terminal motif promoting colony survival also contributes to suppression of the Ser(15) kinase pathway. These data identify anterior gradient-2 as a novel survival factor whose study may shed light on cellular pathways that attenuate the tumor suppressor p53.
Mol Cell Proteomics 2004 Jun
PMID:The Barrett's antigen anterior gradient-2 silences the p53 transcriptional response to DNA damage. 1496 11

Despite the wide range of probes commercially available for interphase fluorescence in situ hybridisation (FISH), the supply of locus-specific probes is limited to genes or chromosomal regions commonly altered in genetic diseases or during carcinogenesis. Generation of these probes is therefore desirable to accommodate individual research requirements. Hence, we detail the methodology required to design and produce custom locus-specific interphase FISH probes for any human genomic region of interest and their application was illustrated in cytogenetic investigations of Barrett's tumourigenesis. Previously utilising FISH, we observed that Barrett's tissues demonstrated chromosome 4 hyperploidy [Gut 52 (2003) 623], but as centromeric probes were used in this analysis, it was not known if the whole chromosome was amplified. We consequently generated single-copy sequence probes for the 4p16.3 and 4q35.1 subtelomeric loci. Multicolour FISH was subsequently performed on interphase preparations originating from patients with Barrett's esophagus at varying histological grades, thus demonstrating the whole region of chromosome 4 was amplified within the tissues. Additionally, probes for the DNA methyltransferase genes were produced to determine if gene dosage alterations were responsible for increasing methylation activity during Barrett's neoplastic progression. No significant alterations at the DNMT1 and DNMT3a loci were detected. An increased copy number of these genes is therefore not the basis for the hypermethylation commonly observed in this premalignant lesion.
Exp Mol Pathol 2004 Aug
PMID:Generation of locus-specific probes for interphase fluorescence in situ hybridisation--application in Barrett's esophagus. 1521 47

Intestinal metaplasia (IM) in endoscopic biopsies obtained from close to the gastroesophageal junction may represent IM of the cardia (CIM) or Barrett's esophagus (BE), which have different malignant potentials despite similar morphology. This study compared cytokeratin (CK) 7/20 and mucin (MUC1, 2, 5AC, and 6) immunopatterns in biopsies from BE (n = 41), CIM (n = 35), and antral gastric IM (AIM, n = 37) to evaluate their roles as diagnostic aids. CK7 and CK20 expression was described as absent, patchy (superficial and deep), continuous superficial only, continuous deep only, and diffuse. Eleven different combinations of CK7/20 expression were seen. Since CK20 staining was positive in all cases, four main patterns were defined on the basis of the observed CK7 staining as 1, absent; 2, patchy (superficial and/or deep); 3, diffuse; and 4, continuous superficial only. Overall CK7 positivity (regardless of pattern) was higher in BE and CIM than in AIM. CK patterns 3 and 4 were also higher in BE and CIM than in AIM. For either pattern 3 or 4, the positive and negative predictive values for BE versus AIM were 95% and 67%, respectively. MUC1 was rarely expressed in BE and CIM compared with AIM, whereas the opposite was noted for MUC5AC expression. MUC2 and MUC6 expression was similar in all locations. In conclusion, diffuse or continuous superficial CK7 staining is highly characteristic of BE and CIM and contrasts with AIM. It is, however, not very sensitive. CK20 profiles have no added value. Mucin expression also differs between BE and CIM versus AIM, but the specificity of any pattern is insufficient for distinction in individual cases. Importantly, CK and MUC expression patterns in BE and CIM are virtually indistinguishable, limiting their use in this differential and raising the question of whether they are biologically related.
Appl Immunohistochem Mol Morphol 2004 Jun
PMID:Cytokeratin 7/20 and MUC1, 2, 5AC, and 6 expression patterns in Barrett's esophagus and intestinal metaplasia of the stomach: intestinal metaplasia of the cardia is related to Barrett's esophagus. 1535 40


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