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  • DKFZ Publication Database  (2,636)
  • Journal article published  (2,635)
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  • PROTEIN  (1,921)
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  • 101
    Keywords: GROWTH ; IN-VITRO ; CELL ; Germany ; IN-VIVO ; KINASE ; VITRO ; VIVO ; GENE ; GENES ; PROTEIN ; PROTEINS ; RNA ; transcription ; COMPLEX ; DNA ; MESSENGER-RNA ; PHOSPHORYLATION ; ASSOCIATION ; antibodies ; antibody ; MOUSE ; CHROMATIN ; REQUIRES ; LOCALIZATION ; NUCLEUS ; OVEREXPRESSION ; POLYMERASE-I ; RNA-POLYMERASE-I ; MOTOR ; RECOMBINANT ; NUCLEAR ACTIN ; FACTOR TIF-IA ; INITIATION-FACTOR
    Abstract: The presence of actin and nuclear myosin I (NMI) in the nucleus suggests a role for these motor proteins in nuclear functions. We have investigated the role of actin and nuclear myosin I ( NMI) in the transcription of ribosomal RNA genes ( rDNA). Both proteins are associated with rDNA and are required for RNA polymerase I (Pol I) transcription. Microinjection of antibodies against actin or NMI, as well as short interfering RNA-mediated depletion of NMI, decreased Pol I transcription in vivo, whereas overexpression of NMI augmented pre-rRNA synthesis. In vitro, recombinant NMI activated Pol I transcription, and antibodies to NMI or actin inhibited Pol I transcription both on naked DNA and pre-assembled chromatin templates. Whereas actin associated with Pol I, NMI bound to Pol I through the transcription-initiation factor TIF-IA. The association with Pol I requires phosphorylation of TIF-IA at Ser 649 by RSK kinase, indicating a role for NMI in the growth-dependent regulation of rRNA synthesis
    Type of Publication: Journal article published
    PubMed ID: 15558034
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  • 102
    Keywords: PEPTIDE ; Germany ; COMMON ; PROTEIN ; PROTEINS ; DOMAIN ; ANTIGEN ; DYNAMICS ; SIMULATION ; SEQUENCE ; SEQUENCES ; antibodies ; antibody ; TARGET ; DESIGN ; VARIABILITY ; VACCINE ; STRATEGIES ; PREDICTION ; GP120 ; MOLECULAR-DYNAMICS ; HIV-1 ; GENOMIC DIVERSITY ; HTLV-III ; MINIMIZATION
    Abstract: The most promising target antigen for an HIV vaccine designed using the classic antibody strategy has been the viral coat protein gp120. Unfortunately, its high variability has prevented this approach. We examine here a 15-residue peptide derived from the CD4-binding domain of gp120. By use of molecular dynamics computer simulation, it is shown that despite considerable sequence variation, the three-dimensional structure of the peptide is preserved over the full range of clade-specific sequences. Furthermore, sequences threaded onto the structure exhibit common three-dimensional electrostatic and hydrophobic properties. These common physicochemical characteristics constitute a pharmacophoric footprint that promises to be useful in the design of a synthetic antigen for vaccine development
    Type of Publication: Journal article published
    PubMed ID: 15239651
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  • 103
    Keywords: CANCER ; EXPRESSION ; tumor ; carcinoma ; CELL ; human ; KINASE ; PATHWAY ; GENE ; GENE-EXPRESSION ; GENES ; EPITHELIA ; DNA ; INFECTION ; CONTRAST ; papillomavirus ; LESIONS ; PROGRESSION ; gene expression ; ASSAY ; smoking ; inactivation ; PCR ; human papillomavirus ; HPV ; HUMAN-PAPILLOMAVIRUS ; SQUAMOUS-CELL CARCINOMA ; HEAD ; NECK ; squamous cell carcinoma ; TOBACCO ; ALCOHOL ; PREVALENCE ; GREECE ; head and neck ; ORAL-CANCER ; NECK-CANCER ; CELL CARCINOMA ; PRIMARY TUMORS ; head and neck cancers,tumor suppressor gene expression,human papillomavirus ; P16
    Abstract: To further characterize the biological and clinical role of molecular alterations involved in oral squamous carcinogenesis, the immunohistochemical expression level of two tumor suppressor genes, fragile histidine triad and p16(INK4a), in non-carcinomatous squamous epithelia and head and neck squamous cell carcinoma was determined. In addition, human papillomavirus infection determined by PCR assay and the use of alcohol and cigarettes were evaluated. In this study 28 non-carcinomatous squamous epithelia and 57 head and neck squamous cell carcinoma were considered. The expression levels of fragile histidine triad were lower in head and neck squamous cell carcinoma than in non-carcinomatous squamous epithelia. In contrast, p16(INK4a) is expressed in malignant lesions (51% of the cases analyzed), but not in non-carcinomatous squamous epithelia. No correlation between gene expression alterations of the two tumor suppressors was observed. PCR analysis showed that HPV DNA was present in 5 of the 57 malignant lesions analyzed (8.8%). None of the factors described above, despite changes in gene expression and HPV infection, appears to be associated with alcohol use and/or tobacco smoking and clinical outcome. Our data showed that fragile histidine triad and p16(INK4a) expression are altered in malignant lesions. Most likely, the decreasing levels of fragile histidine triad is directly involved in cancer development, while the accumulation of p16(INK4a) in head and neck squamous cell carcinoma may be the consequence of loss of functional tumor suppressor retinoblastoma pathway
    Type of Publication: Journal article published
    PubMed ID: 14719099
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  • 104
    Keywords: EXPRESSION ; Germany ; human ; MODEL ; THERAPY ; DIAGNOSIS ; INFORMATION ; NETWORK ; TOOL ; DISEASE ; GENE ; GENES ; GENOME ; PROTEIN ; PROTEINS ; COMPLEX ; COMPLEXES ; BIOLOGY ; SEQUENCE ; FORM ; IDENTIFICATION ; HEALTH ; DATABASE ; PRODUCT ; bioinformatics ; LOCALIZATION ; WEB ; HUMAN GENES ; FUNCTIONAL GENOMICS ; PROTEOMICS ; PRODUCTS ; databases ; ANNOTATION ; RESOURCE ; PROTEIN-ANALYSIS ; FULL-LENGTH HUMAN ; HUMAN CDNAS
    Abstract: As several model genomes have been sequenced, the elucidation of protein function is the next challenge toward the understanding of biological processes in health and disease. We have generated a human ORFeome resource and established a functional genomics and proteomics analysis pipeline to address the major topics in the post-genome-sequencing era: the identification of human genes and splice forms, and the determination of protein localization, activity, and interaction. Combined with the understanding of when and where gene products are expressed in normal and diseased conditions, we create information that is essential for understanding the interplay of genes and proteins in the complex biological network. We have implemented bioinformatics tools and databases that are suitable to store, analyze, and integrate the different types of data from high-throughput experiments and to include further annotation that is based on external information. All information is presented in a Web database (http://www.dkfz.de/LIFEdb). It is exploited for the identification of disease-relevant genes and proteins for diagnosis and therapy
    Type of Publication: Journal article published
    PubMed ID: 15489336
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  • 105
    Keywords: CANCER ; carcinoma ; Germany ; human ; COMMON ; TOOL ; DISTINCT ; GENE ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; RAT ; MEMBER ; MEMBERS ; VARIANTS ; ACID ; antibodies ; antibody ; FORM ; IDENTIFICATION ; immunohistochemistry ; HEPATOMA ; MASS-SPECTROMETRY ; SUPERFAMILY ; CARCINOMAS ; PROTEOMIC ANALYSIS ; GEL-ELECTROPHORESIS ; ALDOSE REDUCTASE ; 2-DIMENSIONAL ELECTROPHORESIS ; REDUCTASE ; TISSUE PROTEINS ; ALDEHYDE REDUCTASE ; ALDO-KETO REDUCTASES ; LIVER-CELL-LINES ; RAT HEPATOMAS ; REDUCTASE GENE-EXPRESSION
    Abstract: The proteomic approach is a valuable tool to detect and identify proteins that are associated with cancer. In previous investigations on experimentally induced rat hepatomas, we detected aldose reductase-like protein (ARLP) as a highly significant marker protein. Our present study was intended to look for the presence of similar tumor-associated marker proteins on human hepatocellular carcinomas (HCC). We found several novel tumor-associated protein variants that represent members of the aldo-keto reductase (AKR) superfamily. Human aldose reductase-like protein-1 (hARLP-1) was the most prominent tumor-associated AKR member detected in HCC by 2-dimensional electrophoresis (2-DE) and identified by mass spectrometric fingerprinting. The enzyme was found in 4 distinct forms (hARLP-1, 36/7.4 (kd/pI); hARLP-2, 36/7.2; hARLP-3, 36/6.4; and hARLP-4, 33/7.35). In addition, a human aldose reductase-like protein (hARLP-5, 36/7.6) was identified that differed from hARLP-1 by 1 amino acid (D313N), indicating 2 allelic forms of the human aldose reductase-like gene. A novel antibody directed against common parts of the hARLPs revealed hARLP reactivity in human HCC by immunohistochemistry. Furthermore, aldose reductase (AR) was identified and characterized as a tumor-associated variant. In conclusion, in all investigated human HCCs at least one of the various types of the described tumor-associated proteins of the AKR superfamily was clearly present. Of these HCC samples, 95% were positive for hARLPs as proven by 2-DE analysis and/or by use of the antibody directed against hARLP. Thus, hARLP is a strong candidate for use as an immunohistochemical diagnostic marker of human HCC
    Type of Publication: Journal article published
    PubMed ID: 14768008
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  • 106
    Keywords: CELLS ; EXPRESSION ; carcinoma ; Germany ; LUNG ; PATHWAY ; DEATH ; PROTEIN ; PROTEINS ; TUMOR-NECROSIS-FACTOR ; MECHANISM ; TRANSCRIPTION FACTOR ; DOMAIN ; CONTRAST ; mechanisms ; SEQUENCE ; VARIANTS ; MOLECULE ; NUCLEI ; MALIGNANCIES ; PATTERNS ; CARCINOMA CELLS ; CELL-DEATH ; DAMAGE ; LOCALIZATION ; MITOCHONDRIA ; LENGTH ; targeting ; SINGLE ; MALIGNANCY ; HUMAN LUNG ; cell death ; DEPENDENT APOPTOSIS ; HEPATOCYTE APOPTOSIS ; HUMAN-PROSTATE ; LYSOSOMAL PATHWAY ; MATURE ; SUBCELLULAR-DISTRIBUTION
    Abstract: Background: Splicing variants of human cathepsinB primary transcripts ( CB(- 2,3)) result in an expression product product which lacks the signal peptide and parts of the propeptide. This naturally truncated Delta(51)CB is thus unable to follow the regular CB processing and sorting pathway. It is addressed to the mitochondria through an activated N-terminal mitochondrial targeting signal instead. Although Delta(51)CB is supposed to be devoid of the typical CB enzymatic activity, it might play a role in malignancies and trigger cell death/apoptosis independent from the function of the regular enzyme. Cytoplasmic presence of the mature CB might occur as a result of lysosomal damage. Results: We investigated such "aberrant" proteins by artificial CB-GFP chimeras covering various sequence parts in respect to their enzymatic activity, their localization in different cell types, and the effects on the cell viability. Unlike the entire full length CB form, the artificial single chain form was not processed and did not reveal typical enzymatic CB activity during transient overexpression in large cell lung carcinoma cells.. Delta(51)CB was found predominantly in mitochondria. In contrast, the shorter artificial CB constructs localized in the cytoplasm, inside the cell nucleus, and in the midbodies of dividing cells. Bleaching experiments revealed both mobile and immobile fractions of these constructs in the nucleus. Nuclear accumulation of artificially truncated CB variants led to disintegration of nuclei, followed by cell death. Conclusion: We propose that cell death associated with CB is not necessarily triggered by its regular enzymatic activity but alternatively by a yet unknown activity profile of truncated CB. Cytoplasmic CB might be able to enter the cell nucleus. According to a mutational analysis, the part of CB that mediates its nuclear import is a signal patch within its heavy chain domain. The results suggest that besides the N-terminal signal peptide also other CB domains contain patterns which are responsible for a differentiated targeting of the molecule, e. g. to the mitochondria, to the nucleus, or to vesicles. We propose a hierarchy of targeting signals depending on their strength and availability. This implies other possible transport mechanisms besides the usual trafficking via the mannose-6-pathway
    Type of Publication: Journal article published
    PubMed ID: 15807897
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  • 107
    Keywords: CANCER ; Germany ; human ; IN-VIVO ; POPULATION ; PROTEIN ; PROTEINS ; MICE ; RESPONSES ; DNA ; INFECTION ; INDUCTION ; ANTIGEN ; ANTIGENS ; T-CELL ; E7 ; papillomavirus ; IMMUNE-RESPONSES ; antibodies ; antibody ; PARTICLES ; virus ; PROGRESSION ; VECTOR ; cervical intraepithelial neoplasia ; CERVICAL-CANCER ; FUSION ; human papillomavirus ; TYPE-16 ; VACCINES ; VIRUS-LIKE PARTICLES ; SURFACE ; MAMMALIAN-CELLS ; VACCINE ; STRATEGIES ; EPITOPES ; IMMUNE-RESPONSE ; IMMUNITY ; hepatitis B virus ; IMMUNOGENICITY ; TARGETS ; ADENOVIRUS ; FUSION PROTEIN ; T-cell response ; YOUNG-WOMEN ; IMMUNIZATION ; RECOMBINANT ; secretion ; ENHANCEMENT ; CARRIER ; CANCER PROGRESSION ; INDUCE ; HEPATITIS-B ; E7 PROTEINS
    Abstract: Induction of effective immune responses may help prevent cancer progression. Tumor-specific antigens, such as those of human papillomaviruses involved in cervical cancer, are targets with limited intrinsic immunogenicity. Here we show that immunization with low doses (10(6) infectious units/dose) of a recombinant human adenovirus type 5 encoding a fusion of the E7 oncoprotein of human papillomavirus type 16 to the carboxyl terminus of the surface antigen of hepatitis B virus (HBsAg) induces remarkable E7-specific humoral and cellular immune responses. The HBsAg/E7 fusion protein assembled efficiently into virus-like particles, which stimulated antibody responses against both carrier and foreign antigens, and evoked antigen- specific kill of an indicator cell population in vivo. Antibody and T-cell responses were significantly higher than those induced by a control adenovirus vector expressing wild-type E7. Such responses were not affected by preexisting immunity against either HBsAg or adenovirus. These data demonstrate that the presence of E7 on HBsAg particles does not interfere with particle secretion, as it occurs with bigger proteins fused to the C terminus of HBsAg, and results in enhancement of CD8(+)-mediated T-cell responses to E7. Thus, fusion to HBsAg is a convenient strategy for developing cervical cancer therapeutic vaccines, since it enhances the immunogenicity of E7 while turning it into an innocuous secreted fusion protein
    Type of Publication: Journal article published
    PubMed ID: 16188983
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  • 108
    Keywords: CANCER ; DIAGNOSIS ; LUNG-CANCER ; HISTORY ; RISK ; GENE ; GENES ; METABOLISM ; GENETIC POLYMORPHISMS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; DELETION ; MUTANT ; GLUTATHIONE ; AGE ; smoking ; cancer risk ; CARRIERS ; case-control studies ; TOBACCO ; CANCER-RESEARCH ; M1 ; glutathione-S-transferase ; GLUTATHIONE S-TRANSFERASE ; case-control study ; ENVIRONMENTAL CARCINOGENS ; GSTM1 ; GSTT1 ; METAANALYSIS ; CLASS-MU ; GSTT1 POLYMORPHISMS
    Abstract: The glutathione S-transferase (GST) genes are involved in the metabolism of various carcinogens. Deletion polymorphisms in the genes GSTM1 and GSTT1 and a base transition polymorphism at codon 105 (Ile--〉Val) in GSTP1 were investigated in relation to breast cancer risk. Tobacco smoking and reproductive factors were examined as potential effect modifiers. Individual data from seven case-control studies were pooled within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens. To measure the effect of GSTs on breast cancer risk, odds ratios and 95% confidence intervals were computed adjusting for study center and age. The modifying effect was investigated by stratification on variables of smoking habits and reproductive history. A total of 2,048 cases with breast cancer and 1,969 controls were analyzed. The relative odds ratio (95% confidence interval) of breast cancer was 0.98 (0.86-1.12) with the GSTM1 null, 1.11 (0.87-1.41) with the GSTT1 null, 1.01 (0.79-1.28) with GSTP1 heterozygous mutants, and 0.93 (0.62-1.38) with GSTP1 homozygous mutants. Stratification by smoking or reproductive factors did not reveal a modifying effect of these variables, nor was there any association between GSTM1 and age at diagnosis of breast cancer. This is the largest study investigating susceptibility to breast cancer due to polymorphisms in the GST genes. The results conclusively show that single gene GST polymorphisms do not confer a substantial risk of breast cancer to its carriers. Furthermore, GSTs did not interact with smoking or reproductive history to modify cancer risk
    Type of Publication: Journal article published
    PubMed ID: 15342448
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  • 109
    Keywords: brain ; CELLS ; CELL ; Germany ; human ; DIAGNOSIS ; SYSTEM ; HYBRIDIZATION ; PROTEIN ; DIFFERENTIATION ; TISSUE ; PATIENT ; DNA ; INFECTION ; CYCLE ; SIGNAL ; SUSCEPTIBILITY ; ACID ; antibodies ; antibody ; PARTICLES ; virus ; STAGE ; IN-SITU ; AMPLIFICATION ; immunohistochemistry ; NUMBER ; PCR ; LYMPHOCYTES ; PRODUCT ; PHENOTYPE ; POLYMERASE-CHAIN-REACTION ; REPLICATION ; CENTRAL-NERVOUS-SYSTEM ; INSITU HYBRIDIZATION ; SECTIONS ; PML ; CLUSTER ; FEATURES ; POLYOMAVIRUS ; AIDS,CD68,double-staining methods,GFAP,HIV,GC,HIV,ISH,PCR,JCV-GC,JC virus,PML ; DEFICIENCY-SYNDROME AIDS ; DEMENTIA COMPLEX ; MULTINUCLEATED GIANT-CELLS
    Abstract: Progressive multifocal leukoencephalopathy (PML), caused by the human polyomavirus JC (JCV), is an opportunistic infection of the central nervous system (CNS), the histopathological diagnosis of which can be made by routine staining. Very low copy numbers of JCV nucleic acid can be detected in paraffin sections by the specific and highly sensitive in situ polymerase chain reaction ( in situ PCR). The authors evaluated JCV infection in 12 acquired immunodeficiency syndrome ( AIDS) patients with PML by comparison of hematoxylin and eosin (H&E) staining, in situ hybridization ( ISH), and in situ PCR. Phenotype of infected cells was determined by immunohistochemistry with antibodies against glial fibrillary acidic protein (GFAP) or cluster of differentiation 68 (CD68), focusing on cells containing low JC viral copy numbers, and on cell types that are normally not associated with papovavirus infection. The number of detectable JCV-positive oligodendrocytes increased markedly upon PCR amplification and hitherto unknown oligodendrocytic staining patterns were discernible: JCV DNA was detectable in both nucleus and cytoplasm, in cytoplasm only, and as ghost-cell silhouettes appearing as a membranous "rim" of staining product in some cells. The authors suggest that the staining patterns correspond to different stages of the viral replication cycle. Some human immunodeficiency virus (HIV)-type giant cells (HIV-GCs) were shown to contain JCV DNA, thus probably revealing a double infection. Macrophages and HIV-GCs showed staining in the cytoplasm and the nuclei, indicating that they not only may phagocytize JCV particles but may also be actively infected. CD68-positive GCs were occasionally noted to contain a complete JCV DNA positive nucleus in their center, and were accordingly called JCV-type giant cells (JCV-GCs). Rarely, JCV DNA signals were noted in vascular endothelium. No JCV infection was detectable in lymphocytes, neurons, or in brain tissue of JCV-negative age-matched controls. The authors report new findings concerning inter- and intracellular JCV infection patterns in PML, possibly shedding new light on JCV susceptibility of different cell types in the brain of AIDS patients with PML
    Type of Publication: Journal article published
    PubMed ID: 14982723
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  • 110
    Keywords: CELLS ; EXPRESSION ; BLOOD ; CELL ; Germany ; human ; PROTEIN ; PROTEINS ; DIFFERENTIATION ; CONTRAST ; BINDING ; fibroblasts ; culture ; VECTORS ; VECTOR ; NUMBER ; RATES ; COMPONENT ; MODULATION ; CANCER-CELLS ; LENGTH ; STEM-CELLS ; telomerase ; PROGENITOR CELLS ; HEMATOPOIETIC PROGENITOR CELLS ; RETROVIRAL VECTORS ; APLASTIC-ANEMIA ; BINDING PROTEIN ; cord blood ; HUMAN-LYMPHOCYTES ; CYTOKINE ; BINDING-PROTEIN ; fibroblast ; CAPACITY ; aging ; LINEAGE ; flow-FISH ; HUMAN BONE-MARROW ; REPLICATIVE LIFE-SPAN ; SERIAL TRANSPLANTATION ; stem cells ; telomere length
    Abstract: Loss of telomeric repeats has been causally linked to replicative senescence and aging in human cells. In contrast to normal somatic cells, which are telomerase-negative, hematopoietic stem cells have low levels of telomerase, which can be transiently upregulated upon cytokine stimulation. To examine whether ectopic expression of telomerase can overcome telomere erosion in hematopoietic progenitor cells, we overexpressed telomerase in CD34(+) and AC133(+) cord blood (CB) cells using retroviral vectors containing hTERT, the catalytic component of telomerase. Although the hTERT-transduced CB cells exhibited significantly elevated telomerase activity (approximately 10-fold), the mean telomere length was only increased up to 600 bp, which was in contrast to hTERT-transduced fibroblast cells gaining more than 2-kb telomeric repeats. Moreover, ectopic telomerase activity did not prevent overall telomere shortening, which was in the range of 1.3 kb in serum-free expansion culture. We also blocked endogenous telomerase activity by ectopic expression of dominant-negative hTERT. Whereas CB cells with absent telomerase activity showed reduced absolute numbers of colony-forming cells, we observed increased rates only for burst-forming units erythroid when the enzyme was overexpressed. These results suggest that telomere shortening in human hematopoietic progenitor cells cannot be compensated by increased levels of telomerase alone and is likely to be dependent on other factors, such as telomere binding proteins. Furthermore, telomerase function seems to be directly associated with the proliferative capacity of stem cells and may exert an additional role in lineage differentiation
    Type of Publication: Journal article published
    PubMed ID: 15342938
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  • 111
    Keywords: human ; FOLLOW-UP ; screening ; GENE ; GENES ; GENOME ; PROTEIN ; DNA ; FAMILY ; ASSOCIATION ; chromosome ; FREQUENCY ; GENOMEWIDE SCREEN ; LINKAGE ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; SUSCEPTIBILITY ; VARIANTS ; ACID ; NUCLEIC-ACIDS ; PATTERNS ; MUTATION ; genetics ; SNP ; REGION ; REGIONS ; LINKAGE DISEQUILIBRIUM ; MUTATIONS ; PERVASIVE DEVELOPMENTAL DISORDERS ; EVOLUTION ; Jun ; INDIVIDUALS ; LIQUID-CHROMATOGRAPHY ; molecular ; RE ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; genomics ; CANDIDATE GENES ; RHEUMATOID-ARTHRITIS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; SCREEN ; association analysis ; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ; autism ; COMMON DISEASE ; GENOTYPE ; HAPLOTYPE ; HAPLOTYPES ; LOCUS ; MOLECULAR-GENETICS ; multiplex ; P63 ; PEDIGREES ; single-nucleotide ; single-nucleotide polymorphism
    Abstract: Autism is a highly heritable neurodevelopmental disorder whose underlying genetic causes have yet to be identified. To date, there have been eight genome screens for autism, two of which identified a putative susceptibility locus on chromosome 16p. In the present study, 10 positional candidate genes that map to 16p11-13 were examined for coding variants: A2BP1, ABAT, BFAR, CREBBP, EMP2, GRIN2A, MRTF-B, SSTR5, TBX6, and UBN1. Screening of all coding and regulatory regions by denaturing high-performance liquid chromatography identified seven non-synonymous changes. Five of these mutations were found to cosegregate with autism, but the mutations are not predicted to have deleterious effects on protein structure and are unlikely to represent significant etiological variants. Selected variants from candidate genes were genotyped in the entire International Molecular Genetics Study of Autism Consortium collection of 239 multiplex families and were tested for association with autism by use of the pedigree disequilibrium test. Additionally, genotype frequencies were compared between 239 unrelated affected individuals and 192 controls. Patterns of linkage disequilibrium were investigated, and the transmission of haplotypes across candidate genes was tested for association. Evidence of single-marker association was found for variants in ABAT, CREBBP, and GRIN2A. Within these genes, 12 single-nucleotide polymorphisms (SNPs) were subsequently genotyped in 91 autism trios (one affected individual and two unaffected parents), and the association was replicated within GRIN2A (Fisher's exact test, P < .0001). Logistic regression analysis of SNP data across GRIN2A and ABAT showed a trend toward haplotypic differences between cases and controls
    Type of Publication: Journal article published
    PubMed ID: 15830322
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  • 112
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; Germany ; TYROSINE KINASE ; EXPOSURE ; PROTEIN ; ACTIVATION ; INFECTION ; INDUCTION ; KERATINOCYTES ; DYNAMICS ; MOLECULE ; PLASMA ; MEMBRANE ; STRESS ; human papillomavirus ; TYPE-16 ; EPITHELIAL-CELL LINE ; GOLGI-APPARATUS ; MHC CLASS-I ; PLASMA-MEMBRANE ; RECEPTORS ; HUMAN FORESKIN KERATINOCYTES ; keratinocyte ; phosphatidylcholine ; plasma membrane ; CERVICAL-CANCER WORLDWIDE ; CHOLESTEROL EFFLUX ; CTP-PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE ; CYCLODEXTRIN ; SPHINGOMYELIN
    Abstract: The E5 protein of the human papillomavirus type 16 is a small protein found associated to membranes, mainly in the Golgi apparatus, and expressed in the early stages of viral infection. Its expression modifies the cell response towards growth factors and stress exposures, and also blocks the surface expression of MHC molecules. A global explanation for these multiple effects is hitherto not available. Here we present data showing that the expression of HPV16-E5 increases the amount of free cholesterol readily extractable from the plasma membrane, without altering the total cholesterol content. In addition, HPV16-E5 modifies the composition of the cell membranes, increasing the synthesis rate of phosphatidylcholine and phosphatidylserine, while diminishing that of phosphatidylglycerol. We propose that these changes in the lipid composition of the membrane are the central effect of HPV16-E5 on the cell. The multiple and apparently disconnected effects of HPV16-E5 on tyrosine-kinase receptors, induction of the apoptosis and impairment of MHC trafficking could follow the initial alteration on the membrane composition
    Type of Publication: Journal article published
    PubMed ID: 15503216
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  • 113
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; VITRO ; DEATH ; GENE ; PROTEIN ; RNA ; LINES ; gene transfer ; GENE-TRANSFER ; MECHANISM ; RAT ; CONTRAST ; mechanisms ; CELL-LINES ; PROTEIN-KINASE ; CLEAVAGE ; resistance ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; MEMBRANE ; LINE ; KAPPA-B ; sensitivity ; OVEREXPRESSION ; cell lines ; CASPASE-8 CLEAVAGE ; SIGNALING COMPLEX ; CASPASE ; INHIBITORS ; RE ; GLIOMA ; CASPASE-8 ; OLIGONUCLEOTIDE ; NEURONS ; C-FLIP ; cell death ; ANTISENSE OLIGONUCLEOTIDE ; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME ; CEREBELLAR GRANULE NEURONS ; Fas/CD95 ; IMMUNE PRIVILEGE ; lifeguard ; PHOSPHATIDYLINOSITOL 3-KINASE ; PI3-kinase/ Akt
    Abstract: The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI3-kinase, overexpression of the inhibitory protein I kappa B, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e. g., inhibition of the PI3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL
    Type of Publication: Journal article published
    PubMed ID: 16033886
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  • 114
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; Germany ; KINASE ; GENE ; GENE-EXPRESSION ; PROTEIN ; DIFFERENTIATION ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; MESSENGER-RNA ; DOMAIN ; mechanisms ; DOWN-REGULATION ; PHOSPHORYLATION ; PROTEIN-KINASE ; signal transduction ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; gene expression ; TRANSCRIPTIONAL ACTIVITY ; SIGNAL-TRANSDUCTION ; CANCER-CELLS ; CARCINOMA-CELLS ; LOCALIZATION ; PROTEIN-KINASE-C ; PHORBOL ESTER ; ESTRADIOL ; SYNTHASE ; TRANSFECTION ; regulation ; ESTROGEN ; estrogen receptor ; GLYCOGEN-SYNTHASE KINASE-3 ; GSK3 ; MCF-7 CELLS ; PKC ; PKC delta
    Abstract: Regulation of estrogen receptor (ER) function in breast cancer cells is a complex process involving different signalling mechanisms. One signal transduction component that appears to influence ER signalling is protein kinase C (PKC). PKC delta is a particular isoenzyme of the novel PKC subfamily that plays a role in growth control, differentiation and apoptosis. The aim of the present study was to investigate the impact of PKC delta on the regulation of the transcriptional activity of the human ER alpha. By using 12-O-tetradecanoylphorbol- 13-acetate (TPA), Bryostatin1 and Rottlerin, we show that active PKC delta is a proproliferative factor in estrogen-dependent breast cancer cells. Furthermore, activation of PKC delta by TPA resulted in activation and nuclear translocation of ER alpha and in an increase of ER-dependent reporter gene expression. Transfection and expression of the regulatory domain RD delta of PKC delta, which is inhibitory to PKC delta, inhibited the TPA-induced ER alpha activation and translocation. ER alpha was not phosphorylated by PKC delta; however, glycogen synthase kinase-3 (GSK3) was identified as a substrate of PKC delta. The expression of RD delta resulted in a decrease of TPA-induced GSK3 phosphorylation and translocation into the nucleus. We suggest that GSK3 plays a role in the PKC delta-related nuclear translocation of ER alpha
    Type of Publication: Journal article published
    PubMed ID: 15824731
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  • 115
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; tumor ; Germany ; KINASE ; GENERATION ; DEATH ; PROTEIN ; MICE ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; mechanisms ; T-CELL ; T-CELLS ; BINDING ; PHOSPHORYLATION ; SUPPRESSION ; ALPHA ; CLEAVAGE ; TRANSGENIC MICE ; activation-induced cell death ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; BETA ; T-LYMPHOCYTES ; sensitization ; TCR ; KAPPA-B ; sensitivity ; SIGNALING COMPLEX ; IMMUNOLOGICAL SYNAPSE ; T lymphocytes ; CD95 ; signaling ; PROGRAM ; RE ; INCREASE ; IMMUNE-SYSTEM ; cell death ; ANTIGEN RECEPTORS ; HPK1 ; progenitor ; INDUCE ; NEGATIVE REGULATION ; SWITCH ; AICD ; CD28 COSTIMULATION ; HEMATOPOIETIC PROGENITOR KINASE-1 ; IKK ; KINASE-C-THETA
    Abstract: Restimulation of the T-cell receptor (TCR) in activated T cells induces CD95 (Fas/Apo-1)-mediated activation-induced cell death (AICD). The TCR-proximal mechanisms leading to AICD are elusive. Here we characterize hematopoietic progenitor kinase 1 (HPK1) as a differentially regulated TCR-proximal signaling protein involved in AICD of primary T cells. We show that HPK1 is a functional component of the endogenous I kappa B kinase (IKK) complex and is crucial for TCR-mediated NF kappa B activation. While full-length HPK1 enhances IKK beta phosphorylation, siRNA-mediated knockdown of HPK1 blunts TCR-mediated NF kappa B activation and increases cell death. We also demonstrate proteolytic processing of HPK1 into HPK1-C, specifically in AICD-sensitive primary T cells. The cleavage product HPK1-C sequesters the inactive IKK complex and suppresses NF kappa B upon TCR restimulation by binding to IKK alpha and IKK beta. T cells of HPK1-C transgenic mice are sensitized towards TCR-mediated AICD. Consequently, preventing HPK1-C generation in primary T cells by siRNA-mediated knockdown results in decreased AICD. Thus, these results show a novel mechanism of sensitization of T lymphocytes towards AICD by suppression of NF kappa B, and propose that HPK1 is a life/death switch in T lymphocytes
    Type of Publication: Journal article published
    PubMed ID: 16341093
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  • 116
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; SURVIVAL ; PROTEIN ; RELEASE ; NF-KAPPA-B ; ACTIVATION ; MECHANISM ; MARKER ; ANTIGEN ; DENDRITIC CELLS ; T-CELLS ; MATURATION ; MOBILITY ; UP-REGULATION ; MARKERS ; LYMPHOCYTES ; SIGNALING PATHWAYS ; Jun ; RAGE ; IMMUNITY ; NEURITE OUTGROWTH ; KAPPA-B ; END ; interaction ; CLASS-II ; dendritic cell ; CHROMATIN PROTEIN HMGB1 ; NECROTIC CELLS
    Abstract: High mobility group box 1 (HMGB1) is an abundant and conserved nuclear protein that is released by necrotic cells and acts in the extracellular environment as a primary proinflammatory signal. In this study we show that human dendritic cells, which are specialized in Ag presentation to T cells, actively release their own HMGB1 into the extracellular milieu upon activation. This secreted HMGB1 is necessary for the up-regulation of CD80, CD83, and CD86 surface markers of human dendritic cells and for IL-12 production. The HMGB1 secreted by dendritic cells is also required for the clonal expansion, survival, and functional polarization of naive T cells. Using neutralizing Abs and receptor for advanced glycation end product-deficient (RAGE(-/-)) cells, we demonstrate that RAGE is required for the effect of HMGB1 on dendritic cells. HMGB1/RAGE interaction results in downstream activation of MAPKs and NF-kappa B. The use of an ancient signal of necrosis, HMGB1, by dendritic cells to sustain their own maturation and for activation of T lymphocytes represents a profitable evolutionary mechanism
    Type of Publication: Journal article published
    PubMed ID: 15944249
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  • 117
    Keywords: SPECTRA ; EXPRESSION ; IN-VITRO ; Germany ; VITRO ; GENE ; GENES ; PROTEIN ; PROTEINS ; PATIENT ; FAMILY ; SKIN ; SEQUENCE ; chromosome ; ACID ; IDENTIFICATION ; MUTATION ; MUTATIONS ; EPIDERMAL DIFFERENTIATION ; PHENOTYPE ; point mutation ; ARACHIDONIC-ACID ; EUROPE ; NOMENCLATURE ; CHROMOSOME 17P13.1 ; GENE-PRODUCT ; molecular ; ENZYME-ACTIVITIES ; ENZYME ; MISSENSE MUTATION ; MUTANTS ; recombinant protein ; SUBFAMILY ; ALOX12B ; ALOXE3 ; COLLODION BABY ; congenital ichthyosis ; genodermatosis ; genotype/phenotype correlation ; hepoxilin ; HEPOXILINS ; LAMELLAR ICHTHYOSIS ; lipoxygenase
    Abstract: Autosomal,recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of severe hereditary keratinization disorders characterized by intense scaling of the whole integument, and differences in color and shape. It is often associated with erythema. To date, six loci for ARCI. have been mapped. Mutations in ALOXE3 and ALOX12B on chromosome 17p13, which code for two different epidermal lipoxygenases, were recently found in patients with ichthyosiform erythroderma from Turkey, France, and North Africa. Here we describe molecular and clinical findings in 17 families with ARCI originating from Central Europe, Turkey, and the Indian subcontinent, with mutations in ALOXE3 or ALOX12B. We identified 11 novel point mutations in ALOX12B (one nonsense mutation and 10 missense mutations) and four different inactivating mutations in ALOXE3. The gene products of ALOX12B and ALOXE3, the epidermal lipoxygenases 12R-LOX and eLOX3 respectively, are preferentially synthesized in the skin. They act in sequence to convert arachidonic acid via 12(R)-HPETE to the corresponding epoxyalcohol, 8(R)-hydroxy,11(R),12(R)-epoxyeicosatrienoic acid. To assess the impairment of enzyme activity, we expressed the mutated genes in vitro and determined the activity of the recombinant proteins toward their genuine substrates. All but one of the recombinant mutants were enzymatically inactive. The characterization of disease-causing mutations in ALOXE3 and ALOX12B and the resulting ARCI phenotypes did not result in clear diagnostic criteria; however, we found a first correlation between the genetic findings and the clinical presentation of ichthyosis
    Type of Publication: Journal article published
    PubMed ID: 16116617
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  • 118
    Keywords: RECEPTOR ; CANCER ; GROWTH ; GROWTH-FACTOR ; proliferation ; tumor ; CELL-PROLIFERATION ; PATHWAY ; RISK ; GENE ; GENES ; PROTEIN ; TUMORS ; RELEASE ; PATIENT ; BINDING ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; COLORECTAL-CANCER ; PROSTATE-CANCER ; cancer risk ; case-control studies ; SOMATOSTATIN ; CANCER PATIENTS ; nutrition ; FACTOR-I ; BINDING PROTEIN ; SERUM ; SINGLE ; IGF-I ; BINDING-PROTEIN ; case-control study ; ASSOCIATIONS ; RE ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; cell proliferation ; development ; GROWTH-FACTOR-I ; BINDING PROTEIN-3 ; LEVEL ; case control studies ; GENOTYPE DATA ; FACTOR (IGF)-I ; PREMENOPAUSAL WOMEN ; IGFBP3 ; insulin-like growth factor ; PLASMA-LEVELS ; SERUM-LEVELS
    Abstract: Insulin-like growth factor-I (IGF-I) stimulates cell proliferation and can enhance the development of tumors in different organs. Epidemiologic studies have shown that an elevated level of circulating IGF-I is associated to increased risk of breast cancer as well as other cancers. Genetic variants affecting the release or biological action of growth hormone (GH), the main stimulator of IGF-I production, may predict circulating levels of IGF-I and have an effect on cancer risk. We tested this hypothesis with a large case-control study of 807 breast cancer patients and 1,588 matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We genotyped 22 common single nucleotide polymorphisms in 10 genes involved in GH production and action (GHRH, GHRHR, SST, SSTR1-SSTR5, POU1F1, and GH1), and in parallel, we measured serum levels of IGF-I and IGFBP-3, its major binding protein, in samples of cases and controls. SST and SSTR2 polymorphisms showed weak but statistically significant associations with breast cancer risk. SSTR5 polymorphisms were associated with IGF-I levels, whereas one polymorphism in GHRHR and one in POU1F1 were associated with IGFBP-3 levels. Our conclusion is that common genetic variation in the GH synthesis pathway, as measured by single nucleotide polymorphisms selected in the present study, is not a major determinant of IGF-I and IGFBP-3 circulating levels, and it does not play a major role in altering breast cancer risk
    Type of Publication: Journal article published
    PubMed ID: 16214911
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  • 119
    Keywords: CANCER ; IRRADIATION ; radiotherapy ; Germany ; TOXICITY ; LUNG-CANCER ; RISK ; RISKS ; GENE ; GENES ; HYBRIDIZATION ; SURGERY ; radiation ; PATIENT ; DNA ; GENETIC POLYMORPHISMS ; SKIN ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; DESIGN ; DNA-REPAIR ; REPAIR ; DAMAGE ; PROBES ; CARRIERS ; CANCER PATIENTS ; body mass index ; NUCLEOTIDE EXCISION-REPAIR ; DNA repair ; radiation sensitivity ; ACID SUBSTITUTION VARIANTS ; radiosensitivity ; MASSES ; RE ; VARIANT ; CAPACITY ; CANCER SUSCEPTIBILITY ; XPD ; ALLELES ; INTERVAL ; DNA repair gene ; DNA repair genes ; GENETIC-POLYMORPHISM ; CARRIER ; GENOTYPE ; HAPLOTYPE
    Abstract: Purpose: Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility. We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg(194) Trp, Arg(280)His, and Arg(399)GIn), APE1 (Asp(148)Glu), and XPD (Lys(751)Gln and Asp(312)Asn), with the risk of acute skin reactions following radiotherapy. Design: We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Results: Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of theAPE1 (148)Glu and the XRCC1 (399)Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1 (148)Glu and XRCC1 (399)GIn alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; P-interaction = 0-009). Conclusion: The XRCC1 (399)Gln or APE1 (148)Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight
    Type of Publication: Journal article published
    PubMed ID: 16000577
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  • 120
    Keywords: EXPRESSION ; INHIBITOR ; tumor ; carcinoma ; Germany ; KINASE ; TYROSINE KINASE ; GENE ; HYBRIDIZATION ; microarray ; PROTEIN ; TISSUE ; TUMORS ; TYROSINE KINASE INHIBITOR ; IN-SITU ; immunohistochemistry ; NUMBER ; PATHOGENESIS ; FISH ; MUTATIONS ; SQUAMOUS-CELL CARCINOMA ; HEAD ; NECK ; PREVALENCE ; FLUORESCENCE ; OVEREXPRESSION ; imatinib ; fluorescence in situ hybridization ; GAINS ; C-KIT ; ADENOID CYSTIC CARCINOMA ; GASTROINTESTINAL STROMAL TUMORS ; INHIBITORS ; in situ hybridization ; salivary gland tumor ; AMPLIFICATIONS ; GLAND ; intensity ; SUBTYPE ; TUMOR TISSUE ; KINASE INHIBITORS ; SUBTYPES ; KIT ; tissue microarray ; tissue microarray analysis
    Abstract: Adenoid cystic carcinoma (ACC) of the salivary gland is characterized by a prolonged but inevitably unfavorable clinical course. Recent studies suggested the transmembrane tyrosine kinase KIT to be involved in ACC pathogenesis. To investigate KIT expression in histologically defined subgroups of ACC and to clarify whether KIT gene copy number gain contributes to KIT overexpression, tumor tissue microarray sections including 55 ACC tumors were analyzed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). The prevalence of positive KIT immunostaining was 89% (49/55). Strong immunostaining of KIT was only found in cribriform and tubular but never in solid subtypes (p = 0.02). Average KIT staining intensity was higher in cribriform and tubular (n = 37) compared to solid (n = 18) ACC subtypes (p = 0.005). FISH analysis revealed copy number gains of the KIT gene in 6.1% (3/49) of tumors analyzed. Our results implicate that specific KIT tyrosine kinase inhibitors such as imatinib, might be used in future therapeutic approaches against subgroups of ACC. (c) 2005 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16054424
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  • 121
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; human ; IN-VIVO ; INHIBITION ; DEATH ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; PROTEINS ; RNA ; LINES ; MICE ; TRANSDUCTION ; NF-KAPPA-B ; COMPLEX ; COMPLEXES ; MECHANISM ; CONTRAST ; hepatocytes ; CELL-LINES ; signal transduction ; SUPPRESSION ; 5-FLUOROURACIL ; ALPHA ; hepatocellular carcinoma ; resistance ; CARCINOMA CELLS ; EFFICACY ; SIGNAL-TRANSDUCTION ; LINE ; CANCER-CELLS ; CARCINOMA-CELLS ; KAPPA-B ; RECEPTORS ; FLOW-CYTOMETRY ; cell lines ; PROTEASOME ; TRAIL ; SIGNALING COMPLEX ; HUMAN HEPATOCYTES ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; CASPASE-8 ACTIVATION ; INHIBITORS ; signaling ; RE ; INTERFERENCE ; CASPASE-8 ; MEDIATED APOPTOSIS ; TUMORICIDAL ACTIVITY ; interaction ; SIGNALING COMPLEXES ; CLINICAL-RELEVANCE ; carcinoma cell ; death receptor
    Abstract: TRAIL exhibits potent anti-tumor activity on systemic administration in mice. Because of its proven in vivo efficacy, TRAIL may serve as a novel anti-neoplastic drug. However, approximately half of the tumor cell lines tested so far are TRAIL resistant, and potential toxic side effects of certain recombinant forms of TRAIL on human hepatocytes have been described. Pretreatment with the proteasome inhibitor MG132 and PS-341 rendered TRAIL-resistant hepatocellular carcinoma (HCC) cell lines but not primary human hepatocytes sensitive for TRAIL-induced apoptosis. We investigated the different levels of possible MG132-induced interference with resistance to apoptotic signal transduction. Although proteasome inhibition efficiently suppressed nuclear factor-kappaB (NF-kappa B) activity, specific suppression of NF-kappa B by mut kappa B alpha failed to sensitize TRAIL-resistant cell lines for TRAIL-induced apoptosis. In contrast to the previously reported mechanism of sensitization by 5-fluorouracil (5-FU), cellular FLICE-inhibitory protein (cFLIP)(L) and cFLIP(S) were markedly upregulated in the TRAIL death inducing signaling complex (DISC) by proteasome inhibitor pretreatment. Compared with 5-FU pretreatment, caspase-8 was more efficiently recruited to the DISC in MG132 pretreated cells despite the presence of fewer death receptors and more cFLIP in the DISC., But downregulation of cFLIP by short interference RNA (siRNA) further sensitized the HCC cell lines. In conclusion, these results show that otherwise chemotherapy-resistant tumor cells can be sensitized for TRAIL-induced apoptosis at the DISC level in the presence of high levels of cFLIP, which suggests the existence of an additional factor that modulates the interaction of FADD and the TRAIL death receptors. Of clinical relevance, proteasome inhibitors sensitize HCC cells but not primary human hepatocytes for TRAIL-induced apoptosis
    Type of Publication: Journal article published
    PubMed ID: 16037944
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  • 122
    Keywords: CANCER ; Germany ; CLASSIFICATION ; EPIDEMIOLOGY ; HISTORY ; GENE ; GENES ; GENOME ; EPITHELIA ; DNA ; INFECTION ; BIOLOGY ; E7 ; SEQUENCES ; virus ; LESIONS ; CERVICAL-CANCER ; REGION ; TYPE-16 ; EVOLUTION ; E6 ; BENIGN ; L1 ; INFECTIONS ; APPEARANCE ; FRAMEWORK ; LIFE-CYCLE ; E7 PROTEINS ; EPITHELIUM ; L2 ; MULTIPLE ALIGNMENTS ; OPEN READING FRAMES
    Abstract: Papillomaviruses (PVs) infect stratified squamous epithelia in vertebrates. Some PVs are associated with different types of cancer and with certain benign lesions. It has been assumed that PVs coevolved with their hosts. However, recently it has been shown that different regions of the genome have different evolutionary histories. The PV genome has a modular nature and appeared after the addition of pre-existent blocks. This order of appearance in the PV genome is evident today in the different evolutionary rates of the different genes, with new genes - E5, E6 and E7 - diverging faster than old genes - E1, E2, L2 and L1. Here, we propose an evolutionary framework aiming to integrate genome evolution, PV biology and epidemiology of PV infections
    Type of Publication: Journal article published
    PubMed ID: 16181783
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  • 123
    Keywords: CELLS ; EXPRESSION ; Germany ; MODEL ; screening ; GENE ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; DOMAIN ; CELL-CYCLE ; antibodies ; antibody ; gene expression ; MEMBRANE ; REGION ; EGG EXTRACTS ; MUSCULAR-DYSTROPHY ; DREIFUSS MUSCULAR-DYSTROPHY ; lamin ; LEM DOMAIN ; embryogenesis ; MASSES ; muscular dystrophy ; SINGLE ; molecular ; DEFICIENCY ; Xenopus laevis ; XENOPUS-LAEVIS ; assembly ; C-ELEGANS ; OOCYTES ; LAEVIS ; ENVELOPE ; TRANSMEMBRANE DOMAIN ; early development ; emerin ; NUCLEAR-MEMBRANE PROTEIN ; oocyte ; POLYPEPTIDE 2
    Abstract: Emerin is an integral protein of the inner nuclear membrane in the majority of differentiated vertebrate cells. In humans, deficiency of emerin causes a progressive muscular dystrophy of the Emery-Dreifuss type. The physiological role of emerin is poorly understood. By screening and sequencing of EST clones we have identified two emerin homologues in Xenopus laevis, Xemerin1 and Xemerin2. Xemerins share with mammalian emerins the N-terminal LEM domain and a single transmembrane domain at the C-terminus. As shown by immunoblot analysis with Xemerin-specific antibodies, both proteins have an apparent molecular mass of 24kDa but differ in their isoelectric points. Xemerin1 and Xemerin2 proteins are not detectable in oocytes nor during early embryogenesis. Protein expression is first found at stage 43 and persists in somatic cells. However, RT-PCR and Northern blot analysis show Xemerin mRNAs of similar to 4.0 kb to be present in oocytes and throughout embryogenesis. During embryogenesis the level of Xemerin mRNAs increases at stage 22 and is particularly abundant in mesodermal and neuro-ectodermal regions of the embryo. These data provide the necessary background to further investigate the role of emerin in nuclear envelope assembly, gene expression and organ development of X. laevis as a model organism. (c) 2005 Elsevier GmbH. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15819409
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  • 124
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; Germany ; IN-VIVO ; MICROSCOPY ; VITRO ; GENE ; PROTEIN ; PROTEINS ; TISSUE ; ACTIVATION ; kidney ; FAMILY ; DOMAIN ; MOUSE ; Drosophila ; MEMBRANE ; NUMBER ; LINE ; SUPERFAMILY ; Jun ; INVOLVEMENT ; OVEREXPRESSION ; HEALTHY ; ORGANIZATION ; electron microscopy ; BINDS ; INHIBITORS ; ELECTRON-MICROSCOPY ; interaction ; MT1-MMP ; MYOBLAST FUSION ; NEPHROTIC SYNDROME
    Abstract: The NEPH family comprises three transmembrane proteins of the Ig superfamily interacting with the glomerular slit diaphragm proteins podocin and ZO-1. NEPH1 binds to nephrin, another component of the slit diaphragm, and loss of either partner causes heavy proteinuria. NEPH2, which is strongly conserved among a large number of species, is also expressed in the kidney; however, its function is unknown. The authors raised NEPH2 antisera. to demonstrate NEPH2 expression in a variety of mouse tissues, including the kidney and a podocyte cell line. The authors localized the expression of NEPH2 to the glomerular slit diaphragm by electron microscopy and show NEPH2 homodimerization and specific interactions with the extracellular domain of nephrin in vitro and in vivo. NEPH1, however, failed to interact with NEPH2. The authors detected immunoreactive NEPH2 in urine of healthy subjects, suggesting that the extracellular domain is cleaved under physiologic conditions. These findings were confirmed in vitro in podocyte cell. culture. Shedding is increased by tyrosine phosphatase inhibitors and diminished by GM6001, an inhibitor of metalloproteinases. Overexpression experiments indicate an involvement of the MT1-matrix metalloproteinase. The results suggest a role for NEPH2 in the organization and/or maintenance of the glomerular slit diaphragm that may differ from the functions of NEPH1 and nephrin
    Type of Publication: Journal article published
    PubMed ID: 15843475
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  • 125
    Keywords: IN-VITRO ; SURVIVAL ; human ; INHIBITION ; VITRO ; SYSTEM ; PROTEIN ; transcription ; DIFFERENTIATION ; MICE ; TRANSCRIPTION FACTOR ; PHOSPHORYLATION ; ELEMENT-BINDING PROTEIN ; NERVOUS-SYSTEM ; TRANSCRIPTION FACTORS ; TRANSGENIC MICE ; immunohistochemistry ; MIGRATION ; PROGENITOR CELLS ; TRACER ; ADULT ; MICE LACKING ; NEURONS ; cell survival ; SPINE ; development ; PHASE ; ADULT MAMMALIAN BRAIN ; adult neurogenesis ; cell differentiation ; CREB PHOSPHORYLATION ; downregulation ; GENERATED NEURONS ; NEURONAL DIFFERENTIATION ; olfactory deafferentation ; PHENOTYPIC DIFFERENTIATION ; radial migration ; SUBEPENDYMAL ZONE ; SUBVENTRICULAR ZONE
    Abstract: The transcription factor cAMP response element-binding protein ( CREB) is involved in multiple aspects of neuronal development and plasticity. Here, we demonstrate that CREB regulates specific phases of adult neurogenesis in the subventricular zone/olfactory bulb (SVZ/OB) system. Combining immunohistochemistry with bromodeoxyuridine treatments, cell tracer injections, cell transplants, and quantitative analyses, we show that although CREB is expressed by the SVZ neuroblasts throughout the neurogenic process, its phosphorylation is transient and parallels neuronal differentiation, increasing during the late phase of tangential migration and decreasing after dendrite elongation and spine formation. In vitro, inhibition of CREB function impairs morphological differentiation of SVZ-derived neuroblasts. Transgenic mice lacking CREB, in a null CREM genetic background, show reduced survival of newborn neurons in the OB. This finding is further supported by peripheral afferent denervation experiments resulting in downregulation of CREB phosphorylation in neuroblasts, the survival of which appears heavily impaired. Together, these findings provide evidence that CREB regulates differentiation and survival of newborn neurons in the OB
    Type of Publication: Journal article published
    PubMed ID: 16267218
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  • 126
    Keywords: CELLS ; EXPRESSION ; proliferation ; tumor ; carcinoma ; KINASE ; DISEASE ; PROTEIN ; DIFFERENTIATION ; TUMORS ; CONTRAST ; ACTIVATED PROTEIN-KINASE ; PHOSPHORYLATION ; BREAST ; IN-SITU ; LESIONS ; immunohistochemistry ; MALIGNANCIES ; PATTERNS ; EPITHELIAL-CELLS ; CARCINOMAS ; INTERCELLULAR COMMUNICATION ; MALIGNANCY ; MOLECULAR-BASIS ; BASAL LAMINA ; breast carcinoma ; connexin43 ; GAP JUNCTIONAL COMMUNICATION ; gap junctions
    Abstract: We applied an antiserum (SA226P) specifically recognizing the phosphorylated form of connexin43 (P-Cx43) to human breast samples including normal breast samples, with fibrocystic disease (FCD), fibroadenomas (FA), in situ and infiltrating carcinomas of all major types, and miscellaneous extramarnmary tumors. The findings were compared with those obtained with commercial antisera recognizing all Cx43 forms (pan-Cx43). A subset of samples was stained for Her2-neu and p44/42 to mitogen-activated protein kinase. Paraffin step sections were used. Immunoblots were performed on frozen samples of a representative subset of cases. In the normal breast, FCD, and FA, SA226P stained strongly and extensively most myoepithelial cells (MECs); luminal cells remained unstained. In proliferative FCD and some cellular FA, SA226P stained MEC and the capillary endothelium (CE). In ductal and lobular in situ carcinomas, SA226P reacted strongly and diffusely with the remaining MEC, the CE, and the transformed luminal cells. SA226P stained all infiltrating carcinomas except the tubular variant. In all breast carcinomas, the CE within and adjacent to tumors and some myofibroblasts stained with SA226P. By contrast, pan-Cx43 stained weakly and sporadically the MEC and rare samples of invasive carcinomas. Notably, Mab p44/42 reacted in parallel with the samples stained with SA226P, whereas reactions with Her2 were negative. Immunoblot findings paralleled those obtained immunohistochemically. We conclude that P-Cx43, restricted to MEC in the normal breast, is up-regulated in the same cells in hyperplasias and dysplasias and FA and is strongly up-regulated in invasive carcinomas. Notably, in some proliferative FCD and in most in situ and infiltrating carcinomas, P-Cx43 is strongly expressed in CE within and adjacent to the lesions but not away from them. These findings were paralleled by the strong nuclear reactions noted with Mab p44/42. These phenomena, although not exclusive to malignancy, are particularly conspicuous in breast carcinomas and seemingly reflect active proliferation associated with abnormal gap junctional intercellular communication. (c) 2005 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15948121
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  • 127
    Keywords: EXPRESSION ; IN-VITRO ; Germany ; TYROSINE KINASE ; DIAGNOSIS ; NETWORKS ; SYSTEM ; TOOL ; DISEASE ; DISEASES ; PROTEIN ; PROTEINS ; TISSUE ; COMPLEX ; COMPLEXES ; RAT ; RATS ; PHOSPHORYLATION ; NERVOUS-SYSTEM ; IDENTIFICATION ; PATTERNS ; NUMBER ; mass spectrometry ; MASS-SPECTROMETRY ; DIETARY ; CENTRAL-NERVOUS-SYSTEM ; HABITS ; protein expression ; POLYACRYLAMIDE GELS ; GEL-ELECTROPHORESIS ; MASSES ; development ; PART ; MASS ; 2-DE ; ADULT-RAT ; enteric nervous system ; ENTERIC NERVOUS-SYSTEM ; MALDI-TOF mass spectrometry ; myenteric plexus ; peripheral nervous system ; PHOSPHOPROTEIN ; Sprague Dawley rats ; STATHMIN ; two-dimensional gel electrophoresis (2-DE)
    Abstract: The enteric nervous system in vertebrates is the most complex part of the peripheral nervous system. Concerning chemical coding, ultrastructure and neuronal circuits, it is more similar to the central than to the peripheral nervous system. Its networks, the myenteric and submucous plexus are integrated in the gut wall. The enteric nervous system is a system of high plasticity, which not only changes during pre- and postnatal development, but also with disease or changing dietary habits. The Aim of this study was to elucidate changes in protein expression during the first two postnatal weeks in the rat myenteric plexus. Colonic and duodenal myenteric plexus from newborn (P1) and fourteen-day old (P14) Sprague-Dawley rats was isolated following a procedure that combines enzymatic digestion and mechanical agitation. The neuronal tissue was collected and processed for two-dimensional gel electrophoresis (2-DE). The obtained 2-D gels were stained with silver for image analysis or with colloidal Coomassie for subsequent protein identification. Gels from the various samples showed a high degree of consistence concerning protein-spots found in all preparations. Nevertheless, there was a number of proteins that were clearly detected in one sample but not, or only in significantly smaller amounts in the other. Several differentially expressed proteins in the postnatal myenteric plexus were identified with MALDI-TOF mass spectrometry. Especially stathmin, polyubiquitin and heterogeneous nuclear ribonucleoprotein seem to play an important role in pre- and postnatal development. 2-DE combined with mass spectrometry can help to identify pathological relevant proteins in the enteric nervous system, and so deliver a valuable tool for the early diagnosis of also central nervous system diseases by using biopsies from the gut. (c) 2005 Elsevier B.V All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16183334
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  • 128