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  • DKFZ Publication Database  (15)
  • PROTEIN  (10)
  • GENE  (6)
  • immunohistochemistry  (6)
  • INFLAMMATORY-BOWEL-DISEASE  (5)
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  • DKFZ Publication Database  (15)
Keywords
  • 1
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; human ; SYSTEM ; DISTINCT ; PROTEIN ; EPITHELIA ; MOLECULES ; TISSUE ; TISSUES ; SKIN ; GLYCOPROTEIN ; ELEMENTS ; SURFACE ; LOCALIZATION ; GLANDS ; SEGMENTS ; calnexin ; ESTABLISHMENT ; MUCINS ; salivary gland ; sebaceous gland ; SEBACEOUS GLANDS
    Abstract: Calnexin (Cnx) has been characterized as a membrane-bound protein that transiently interacts in a unique chaperone system with newly synthesized glycoproteins in order to allow the establishment of their proper tertiary and, in most cases, quarternary structures. The aim of the study was to identify and to locate the expression of Cnx in the three major salivary glands of humans by different methods. Strong expression of Cnx protein and mRNA were generally found in serous salivary secretory units. With regard to mucous secretory units, expression of Cnx was only detectable at a low level in mucous acinar cells of sublingual glands, but not of submandibular glands. Expression of Cnx was always preserved in the surface epithelium of intralobar and interlobular duct segments. In addition, expression of Cnx was detected in sebaceous glands of parotid tissues, with a distribution pattern resembling that seen in sebaceous glands of the normal skin. In conclusion, production of saliva is associated with the expression of Cnx. Synthesis of molecules in mucous secretory units is not necessarily associated with a strong Cnx expression, whereas synthesis in serous secretory units apparently is. The tissue- specific Cnx expression is also paralleled by the observation that the secretions produced by the major salivary glands differ in their composition and amount
    Type of Publication: Journal article published
    PubMed ID: 12507291
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  • 2
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; DEATH ; CLONING ; GENE-EXPRESSION ; PROTEIN ; SAMPLE ; SAMPLES ; DIFFERENTIATION ; LIGAND ; MECHANISM ; CONTRAST ; mechanisms ; IN-SITU ; NEOPLASIA ; CELL-DEATH ; DECREASE ; RECEPTORS ; SMALL-INTESTINE ; TRAIL ; protein expression ; LACKING ; molecular ; RECOMBINANT ; MOLECULAR-MECHANISM ; VARIANT ; INCREASE ; CELL-SURFACE EXPRESSION ; PH ; regulation ; development ; MOLECULAR-MECHANISMS ; methods ; cell death ; CELIAC-DISEASE ; death receptor ; USA ; LIGAND TRAIL ; HOMEOSTASIS ; INCREASES ; apoptotic ; MUCOSAL ; ACYL-COA-SYNTHETASE-5 ; HUMAN SMALL-INTESTINE ; IMPAIRED EXPRESSION
    Abstract: Background & Aims: The constant renewal of enterocytes along the crypt-villus axis (CVA) of human small intestine is due to cell-inherent changes resulting in the apoptotic cell death of senescent enterocytes. The aim of the present study was to examine underlying molecular mechanisms of the cell death at the villus tip. Methods: Characterization of human acyl-coenzyme A (CoA) synthetase 5 (ACSL5) was performed by cloning, recombinant protein expression, biochemical approaches, and several functional and in situ analyses. Results: Our data show that different amounts of acyl-CoA synthetase 5-full length (ACSL5-fl) and a so far unknown splice variant lacking exon 20 (ACSL5-Delta 20) are found in human enterocytes. In contrast with the splice variant ACSL5-Delta 20, recombinant and purified ACSL5-fl protein is active at a highly alkaline pH. Over expression of ACSL5-fl protein is associated with a decrease of the anti-apoptotic FLIP protein in a ceramide-dependent manner and an increased cell-surface expression of the death receptor TRAIL-RI. Expression analyses revealed that the ACSL5-fl/ACSL5-Delta 20 ratio increases along the CVA, thereby sensitizing ACSL5-fl-dominated cells at the villus tip to the death ligand TRAIL, which is corroborated by functional studies with human small intestinal mucosal samples and an immortalized human small intestinal cell fine. Conclusions: Our results suggest an ACSL5-dependent regulatory mechanism that contributes to the cellular renewal along the CVA in human small intestine. Deregulation of the ACSL5-fl/ACSL5-Delta 20 homeostasis in the maturation and shedding of cells along the CVA might also be of relevance for the development of intestinal neoplasia
    Type of Publication: Journal article published
    PubMed ID: 17681178
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  • 3
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; INHIBITOR ; carcinoma ; CELL ; Germany ; INHIBITION ; THERAPY ; LUNG-CANCER ; GENE ; PROTEIN ; SAMPLE ; SAMPLES ; TISSUE ; kidney ; FAMILY ; tumour ; ALPHA ; TARGET ; ISOFORM ; immunohistochemistry ; DIFFERENCE ; resistance ; CANCER-CELLS ; BETA ; STRATEGIES ; IMMUNOTHERAPY ; NORMAL TISSUE ; sensitivity ; OVEREXPRESSION ; CANCER-THERAPY ; protein expression ; TRANSCRIPTS ; CELL CARCINOMA ; renal cell carcinoma ; ONCOLOGY ; ADULT ; RE ; THERAPIES ; INCREASE ; cancer therapy ; REAL-TIME ; SURVIVIN ; NUCLEAR ; ML-IAP ; inhibitor of apoptosis ; apoptotic ; quantitative ; livin/ML-IAP ; APOPTOSIS PROTEIN ; CYTOPLASM ; tumour therapy ; Livin/ML-IAP/KIAP ; MELANOMA INHIBITOR
    Abstract: The antiapoptotic Livin/ML-IAP gene has recently gained much attention as a potential new target for cancer therapy. Reports indicating that livin is expressed almost exclusively in tumours, but not in the corresponding normal tissue, suggested that the targeted inhibition of livin may present a novel tumour-specific therapeutic strategy. Here, we compared the expression of livin in renal cell carcinoma and in non-tumorous adult kidney tissue by quantitative real-time reverse transcription-PCR, immunoblotting, and immunohistochemistry. We found that livin expression was significantly increased in tumours (P=0.0077), but was also clearly detectable in non-tumorous adult kidney. Transcripts encoding Livin isoforms alpha and beta were found in both renal cell carcinoma and normal tissue, without obvious qualitative differences. Livin protein in renal cell carcinoma samples exhibited cytoplasmic and/or nuclear staining. In non-tumorous kidney tissue, Livin protein expression was only detectable in specific cell types and restricted to the cytoplasm. Thus, whereas the relative overexpression of livin in renal cell carcinoma indicates that it may still represent a therapeutic target to increase the apoptotic sensitivity of kidney cancer cells, this strategy is likely to be not tumour-specific
    Type of Publication: Journal article published
    PubMed ID: 17968430
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; human ; SYSTEM ; SITE ; GENE ; GENES ; HYBRIDIZATION ; SAMPLE ; PATIENT ; COMPLEX ; BINDING ; BIOLOGY ; MOLECULAR-BIOLOGY ; ASSOCIATION ; DISORDER ; polymorphism ; VARIANTS ; TARGET ; IN-SITU ; ASSAY ; MUTATION ; genetics ; etiology ; REGION ; REGIONS ; REPLICATION ; HEALTHY ; LUCIFERASE ; heredity ; ANTAGONIST ; MANAGEMENT ; molecular biology ; molecular ; DISORDERS ; VARIANT ; NEURONS ; analysis ; EPITHELIUM ; pooled analysis ; HTR3A ; ENGLAND ; MUTATION ANALYSIS ; DYSFUNCTION ; UNTRANSLATED REGION ; POOLED-ANALYSIS ; UK ; 5-HT3 ; ABDOMINAL-PAIN ; ALOSETRON
    Abstract: Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novel HTR3E 3'-UTR variant c.*76G 〉 A (rs62625044) was associated with female IBS-D (P = 0.033, OR = 8.53). This association was confirmed in a replication study, including 119 IBS-D patients and 195 controls from Germany (P = 0.0046, OR = 4.92). Pooled analysis resulted in a highly significant association of c.*76G 〉 A with female IBS-D (P = 0.0002, OR = 5.39). In a reporter assay, c.*76G 〉 A affected binding of miR-510 to the HTR3E 3'-UTR and caused elevated luciferase expression. HTR3E and miR-510 co-localize in enterocytes of the gut epithelium as shown by in situ hybridization and RT-PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with a cis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D
    Type of Publication: Journal article published
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  • 5
    Keywords: CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; GENE-EXPRESSION ; PROTEIN ; transcription ; METABOLISM ; EPITHELIA ; MONOCLONAL-ANTIBODY ; TISSUE ; TUMORS ; TISSUES ; SEQUENCE ; ACID ; ACIDS ; antibodies ; antibody ; ADENOMAS ; SURFACE ; MONOCLONAL-ANTIBODIES ; EPITHELIAL-CELLS ; fatty acids ; FATTY-ACIDS ; adenocarcinoma ; ADENOCARCINOMAS ; carcinoma,epithelial tumors,fatty acid metabolism,small intestine ; CHAIN ACYL-COA ; DEPENDENT REGULATION ; fatty acid metabolism ; SMALL-INTESTINE
    Abstract: Fatty acids are implicated in tumorigenesis, but data are limited concerning endogenous fatty acid metabolism of tumor cells in adenomas and adenocarcinomas of the small intestine. The recently cloned human acyl-CoA-synthetase 5 (ACS5) is predominantly found in the small intestine and represents a key enzyme in providing cytosolic acyl-CoA thioesters. Protein synthesis and mRNA expression of ACS5 were studied in human intestinal tissues using different methods, including a newly established monoclonal antibody. In the healthy small intestine, expression of ACS5 was restricted to the villus surface epithelium but was not detectable in enterocytes lining crypts. ACS5 protein and mRNA were progressively diminished in epithelial cells of adenomas and adenocarcinomas of the small intestine. In conclusion, altered expression of ACS5 is probably related to the adenoma-carcinoma sequence of small intestinal epithelial tumors due to an impaired acyl-CoA thioester synthesis. (C) 2003 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 14608540
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  • 6
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; human ; DIAGNOSIS ; screening ; DISEASE ; PROTEIN ; DIFFERENTIATION ; MONOCLONAL-ANTIBODY ; TISSUE ; MECHANISM ; TISSUES ; mechanisms ; antibodies ; antibody ; IDENTIFICATION ; DECREASE ; PATHOGENESIS ; MONOCLONAL-ANTIBODIES ; EPITHELIAL-CELLS ; PHENOTYPE ; PROTEIN LEVELS ; CROHNS-DISEASE ; MUCOSA ; INFLAMMATORY-BOWEL-DISEASE ; COLITIS ; ACS5,fatty acid metabolism,human,small intestine ; FATTY-ACID PATTERN ; GASTRIC METAPLASIA ; PYLORIC METAPLASIA ; TRIACSIN-C
    Abstract: Several disorders of the small intestine are associated with disturbances in villus architecture. Thus, an understanding of the molecular mechanisms associated with the differentiation of villi represents an important step in the improvement of the understanding of small intestinal pathology. Screening of antibodies from a hybridoma library led to the identification of an acyl-CoA synthetase 5-specific monoclonal antibody. Protein synthesis, mRNA expression, and the enzyme activity of acyl-CoA synthetase 5 were studied by several methods in human small intestinal tissues with Crohn's disease or coeliac disease, respectively. Acyl-CoA synthetase 5 mRNA and protein levels were substantially reduced in injured small intestinal mucosa. Moreover, impaired synthesis of the acyl-CoA synthetase 5 protein was reflected by a decrease in intramucosal enzyme activity. Subtle changes of the acyl-CoA synthetase 5 pattern correlate with conversion of intestinal epithelial cells to a gastric phenotype. These results suggest that deranged acyl-CoA synthetase 5 expression, synthesis, and activity are closely related to the state of villus architecture and epithelial homeostasis in human small intestine. Copyright (C) 2004 John Wiley Sons, Ltd
    Type of Publication: Journal article published
    PubMed ID: 14743501
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  • 7
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; INVASION ; tumor ; CELL ; Germany ; VITRO ; DISEASE ; GENE ; PROTEIN ; PROTEINS ; COMPONENTS ; TUMORS ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; BINDING ; RECOGNITION ; TARGET ; MUTATION ; COMPONENT ; LINE ; MUTATIONS ; EPITHELIAL-CELLS ; FACTOR-KAPPA-B ; NF-kappa B ; TNF-ALPHA ; SALIVARY AGGLUTININ ; SURFACTANT PROTEIN-D ; INFLAMMATORY-BOWEL-DISEASE ; MALIGNANT BRAIN-TUMORS ; SCAVENGER RECEPTOR ; CYTOKINE ; BRAIN-TUMORS ; STREPTOCOCCUS-MUTANS ; secretion ; PATHOGENS ; USA ; function ; immunology ; INHIBIT ; CYSTEINE-RICH DOMAINS ; DYSFUNCTION ; PURPLE SEA-URCHIN ; SEROTYPE-C STRAIN
    Abstract: Mucosal epithelial cell layers are constantly exposed to a complex resident microflora. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by pathogen binding. This report describes the regulation and function of DMBT1 in intestinal epithelial cells, which form the primary immunological barrier for invading pathogens. We report that intestinal epithelial cells up-regulate DMBT1 upon proinflammatory stimuli (e.g., TNF-alpha, LPS). We demonstrate that DMBT1 is a target gene for the intracellular pathogen receptor NOD2 via NF-kappa B activation. DMBT1 is strongly up-regulated in the inflamed intestinal mucosa of Crohn's disease patients with wild-type, but not with mutant NOD2. We show that DMBT1 inhibits cytoinvasion of Salmonella enterica and LPS- and muramyl dipeptide-induced NF-kappa B activation and cytokine secretion in vitro. Thus, DMBT1 may play an important role in the first line of mucosal defense conferring immune exclusion of bacterial cell wall components. Dysregulated intestinal DMBT1 expression due to mutations in the NOD2/CARD15 gene may be part of the complex pathophysiology of barrier dysfunction in Crohn's disease
    Type of Publication: Journal article published
    PubMed ID: 17548659
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  • 8
    Keywords: RECEPTOR ; EXPRESSION ; DISEASE ; GENE ; GENES ; RNA ; MICROARRAY DATA ; innate immunity ; INFLAMMATORY-BOWEL-DISEASE ; inflammatory bowel disease ; laser microdissection ; pattern recognition receptor ; RIG-I ; EXPRESSION DATA ; ARRAYEXPRESS ; Crohn's disease ; NOD2 CARD15 MUTATIONS ; PUBLIC REPOSITORY ; retinoic acid-inducible gene I
    Abstract: BACKGROUND: A defective innate immune response may contribute to the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). Employing a global gene expression analysis, this study was aimed at identifying specifically regulated genes within the epithelial compartment in inflammatory bowel disease (IBD). METHODS: The epithelial fraction of human ileal mucosa samples from surgical specimens was obtained by laser microdissection. Gene expression was examined by global expression profiling (n = 18, Affymetrix), quantitative reverse-transcription polymerase chain reaction (RT-PCR) (n = 35), immunoblot analysis (n = 9), and immunohistochemistry (n = 25). RESULTS: Global expression profiling revealed a pronounced downregulation of the retinoic acid-inducible gene I (RIG-I) within the epithelial layer of the ileum in patients with CD but not with UC. The downregulation of RIG-I was confirmed by quantitative RT-PCR, immunoblot analysis, and immunohistochemistry. CONCLUSIONS: Epithelial downregulation of RIG-I, a known pattern recognition receptor for viral components, might contribute to alterations of the innate mucosal immune response, particularly in CD.
    Type of Publication: Journal article published
    PubMed ID: 21213277
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  • 9
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; IONIZING-RADIATION ; radiotherapy ; COMBINATION ; Germany ; PATHWAY ; PATHWAYS ; PROTEIN ; MOLECULES ; SURGERY ; PATIENT ; ACTIVATION ; primary ; SEQUENCE ; MOLECULE ; CLEAVAGE ; FORM ; immunohistochemistry ; PATTERNS ; CELL-DEATH ; Western-blot ; colorectal cancer ; RATES ; RECURRENCE ; RT-PCR ; adenocarcinoma ; ADENOCARCINOMAS ; beta-catenin ; western blot ; GREECE ; C-MYC ; PATTERN ; ENHANCED EXPRESSION ; FOCAL CEREBRAL-ISCHEMIA ; mesorectal excision ; MYC-INDUCED APOPTOSIS ; neoadjuvant radiotherapy ; PREOPERATIVE RADIOTHERAPY ; RADIATION-INDUCED APOPTOSIS
    Abstract: Recent surgical concepts for primary rectal cancer include the combination of surgery and short-term neoadjuvant radiotherapy (STNR). This is usually given in a dose of 25 Gy over five days in order to reduce local recurrence rates. Clinical studies have shown that local recurrence is found in some patients despite STNR. We identified molecular patterns of the Wnt- and apoptosis pathways as well as expression of junction-associated molecules in rectal cancer specimens of patients who received STNR and in those who did not. Expression patterns were examined by immunohistochemistry and molecular techniques such as LightCycler RT-PCR and Western blot analysis in 25 sporadic rectal adenocacrinoma specimens derived from STNR-patients or non-pretreated donors, respectively. The molecular pattern in response to STNR was heterogeneous and was reflected by responders who show activation of apoptosis and cellular remodeling, whereas the group of non-responders from STNR did not show such reaction and was very similar to untreated controls. Enhanced expression of beta-catenin was generally mediated by STNR, but exclusively in the responder group impaired expression of c-Myc and junction-associated molecules as well as cleavage of poly-ADP-ribose polymerase and of the caspase substrate cytokeratin 19 were found. The molecular profile suggests that STNR interferes with Writ-signaling and c-Myc expression. STNR in its present form is not suitable to fully complete the sequence of apoptosis in all rectal adenocarcinomas
    Type of Publication: Journal article published
    PubMed ID: 15547689
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  • 10
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; IN-VIVO ; VIVO ; DISEASE ; RISK ; GENOME ; HYBRIDIZATION ; PROTEIN ; SAMPLE ; TISSUE ; TUMORS ; MICE ; PATIENT ; DOMAIN ; GENETIC POLYMORPHISMS ; TISSUES ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; DELETION ; IN-SITU ; prevention ; immunohistochemistry ; UP-REGULATION ; NUMBER ; PATHOGENESIS ; DISPLAY ; HUMAN GENOME ; SURFACE ; EPITHELIAL-CELLS ; genetic polymorphism ; NORMAL TISSUE ; CHAIN-REACTION ; SMALL-INTESTINE ; ULCERATIVE-COLITIS ; TERMINAL DIFFERENTIATION ; inflammation ; SALIVARY AGGLUTININ ; SURFACTANT PROTEIN-D ; INFLAMMATORY-BOWEL-DISEASE ; MALIGNANT BRAIN-TUMORS ; SCAVENGER RECEPTOR ; in situ hybridization ; CHAIN ; BRAIN-TUMORS ; pathogen ; VARIANT ; ALLELE ; inflammatory bowel disease ; LEVEL ; methods ; SUBTYPES ; SULFATE ; USA ; function ; INCREASED RISK ; odds ratio ; in vivo ; case control ; quantitative ; MUCOSAL ; EXONS ; CRP-DUCTIN ; DEXTRAN SULFATE SODIUM
    Abstract: Background & Aims: Impaired mucosal. defense plays an important role in the pathogenesis of Crohn's disease (CD), one of the main subtypes of inflammatory bowel disease (IBD). Deleted in malignant brain tumors 1(DMBT1) is a secreted scavenger receptor cysteine-rich protein with predominant expression in. the intestine and has been proposed to exert possible functions in regenerative processes and pathogen defense. Here, we aimed at analyzing the role of DMBT1 in IBD. Methods: We studied DMBT1 expression in IBD and normal tissues by quantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and mRNA in situ hybridization. Genetic polymorphisms within DMBT1 were analyzed in an Italian IBD case-control sample. Dmbt1(-/-) mice were generated, characterized, and analyzed for their susceptibility to dextran sulfate sodium-induced colitis. Results: DMBT1 levels correlate with disease activity in inflamed IBD tissues. A highly significant fraction of the patients with IBD displayed up-regulation of DMBT1 specifically in the intestinal epithelial surface cells and Paneth cells. A deletion allele of DMBT1 with a reduced: number of scavenger receptor cysteine-rich domain coding exons is associated with an increased risk of CD (P =.00056; odds ratio, 1.75) but not for ulcerative colitis. Dmbt1(-/-) mice display enhanced susceptibility to dextran sulfate sodium-induced colitis and elevated Tnf, Il6, and Nod2 expression levels during inflammation. Conclusions: DMBT1 may play a role in intestinal mucosal protection and prevention of inflammation. Impaired DMBT1 function may contribute to the pathogenesis of CD
    Type of Publication: Journal article published
    PubMed ID: 17983803
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