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  • 1
    Keywords: EXPRESSION ; CLONING ; GENE ; PROTEIN ; COMPONENTS ; MICE ; SKIN ; TANDEM MASS-SPECTROMETRY ; fatty acid metabolism ; epidermal barrier ; epidermis ; ACYL-COA SYNTHETASE ; BARRIER FUNCTION ; ceramides ; Fatp4 ; fatty acid transport ; PERMEABILITY BARRIER ; STRATUM- CORNEUM ; TIGHT JUNCTIONS
    Abstract: The fatty acid transport protein family is a group of evolutionarily conserved proteins that are involved in the cellular uptake and metabolism of long and very long chain fatty acids. However, little is known about their respective physiological roles. To analyze the functional significance of fatty acid transport protein 4 (Fatp4, Slc27a4), we generated mice with a targeted disruption of the Fatp4 gene. Fatp4-null mice displayed features of a neonatally lethal restrictive dermopathy. Their skin was characterized by hyperproliferative hyperkeratosis with a disturbed epidermal barrier, a flat dermal-epidermal junction, a reduced number of pilo-sebaceous structures, and a compact dermis. The rigid skin consistency resulted in an altered body shape with facial dysmorphia, generalized joint flexion contractures, and impaired movement including suckling and breathing deficiencies. Lipid analysis demonstrated a disturbed fatty acid composition of epidermal ceramides, in particular a decrease in the C26:0 and C26: 0-OH fatty acid substitutes. These findings reveal a previously unknown, essential function of Fatp4 in the formation of the epidermal barrier
    Type of Publication: Journal article published
    PubMed ID: 12821645
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  • 2
    Keywords: CANCER ; Germany ; QUANTIFICATION ; TOOL ; RISK ; GENE ; SAMPLE ; SAMPLES ; TUMORS ; PATIENT ; DNA ; RISK-FACTORS ; MUTATION ; risk factors ; leukemia ; DNA methylation ; RISK FACTOR ; DERIVATIVES ; PARAMETERS ; FLUORESCENCE ; CYTOSINE METHYLATION ; CD38 EXPRESSION ; HYPERMETHYLATION ; 5-METHYLCYTOSINE CONTENT ; TUMORIGENESIS ; HEAVY ; chronic lymphocytic leukemia ; MUTATION STATUS ; 5-methylcytosine ; CPG ISLANDS ; capillary electrophoresis - laser induced fluorescence ; CAPILLARY-ELECTROPHORESIS ; GENOMIC HYPOMETHYLATION ; immunoglobulin variable heavy chain gene homology
    Abstract: Changes in the genomic DNA methylation level have been found to be closely associated with tumorigenesis. In order to analyze the relation of aberrant DNA methylation to clinical and biological risk factors, we have determined the cytosine methylation level of 81 patients diagnosed with chronic lymphocytic leukemia (CLL). The analysis was based on DNA hydrolysis followed by derivatization of the 2'-desoxyribonucleoside-3'-monophosphates with BODIPY FL EDA. Derivatives were separated by micellar electrokinetic chromatography, and laser-induced fluorescence was used for detection. We analyzed potential correlations between DNA methylation levels and numerous patient parameters, including clinical observations and biological data. As a result, we observed a significant correlation with the immunoglobulin variable heavy chain gene (VH) mutation status. This factor has been repeatedly proposed as a reliable prognostic marker for CLL, which suggests that the methylation level might be a valuable factor in determining the prognostic outcome of CLL. We are now in the process of refining our method to broaden its application potential. In this context, we show here that the oxidation of the fluorescence marker in the samples and the evaporation of methanol in the electrolytes can be prevented by a film of paraffin oil. In summary, our results thus establish capillary electrophoresis as a valuable tool for analyzing the DNA methylation status of clinical samples
    Type of Publication: Journal article published
    PubMed ID: 15188237
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  • 3
    Keywords: CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; Germany ; SYSTEM ; GENE ; PROTEIN ; transcription ; PATIENT ; MECHANISM ; recombination ; cytokines ; MATURATION ; DELETION ; NERVOUS-SYSTEM ; immunohistochemistry ; LYMPHOMA ; MUTATION ; DELETIONS ; REGION ; Jun ; CENTRAL-NERVOUS-SYSTEM ; SERIES ; SOMATIC HYPERMUTATION ; TRANSCRIPTS ; ABSENCE ; immunoglobulin ; FRACTION ; PHASE ; AID ; LYMPHOMAS ; transcript ; SWITCH ; REARRANGEMENTS ; HYPERMUTATION ; CENTER B-CELLS ; GERMINAL-CENTER ; INDUCED CYTIDINE DEAMINASE
    Abstract: Primary lymphomas of the central nervous system (PCNSLs) were investigated for their capacity to perform further maturation steps. We studied a series of 11 PCNSLs derived from immunocompetent patients for immunoglobulin (1g) class switch recombination (CSR) by performing reverse transcriptase-polymerase chain reaction (RT-PCR) for transcripts of Ig constant region gene segments (IGHC). This analysis revealed exclusive transcription of IgM and IgD MRNA in the absence of IgG, IgA, or IgE transcription. This finding was corroborated at the protein level by the immunohistochemical demonstration of IgM on the surface of the tumor cells. The unexpected lack of CSR may be due to internal switch p region deletions, which were detected in 7 of 11 cases. We also found that expression of activation-induced cytidine deaminase (AID), which is required for CSR and somatic hypermutation, was detectable by RT-PCR in 4 of 10 cases and by immunohistochemistry in one of three cases analyzed. This may indicate that ongoing somatic mutation, which is often observed in PCNSL, could be due to sustained AID expression in a fraction of cases and that intraclonal V gene diversity may occur in other cases at an earlier phase of tumor clone expansion, when AID may have been expressed
    Type of Publication: Journal article published
    PubMed ID: 15920162
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  • 4
    Keywords: CANCER ; EXPRESSION ; Germany ; GENE ; PROTEIN ; PROTEINS ; transcription ; TISSUE ; SURGERY ; LINES ; PATIENT ; COMPLEX ; DOMAIN ; tumour ; CELL-LINES ; SEQUENCE ; PROGRESSION ; ASSAY ; Drosophila ; colorectal cancer ; COLORECTAL-CANCER ; metastases ; LINE ; REGION ; MUTATIONS ; ADHESION ; MIGRATION ; cytoskeleton ; POLYMERASE-CHAIN-REACTION ; cell lines ; CELL-MIGRATION ; BINDS ; CELL POLARITY ; MAPS ; colon cancer ; TUMORIGENESIS ; cell adhesion ; cell migration ; ASSAYS ; SUPPRESSOR ; tumour suppressor ; APC ; 17P11.2 ; Hugl-1 ; II HEAVY-CHAIN ; LETHAL-GIANT-LARVAE ; lgl
    Abstract: The human gene, human giant larvae (Hugl-1/Llg1/Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal( 2) giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcription polymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC progression
    Type of Publication: Journal article published
    PubMed ID: 15735678
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  • 5
    Keywords: EXPRESSION ; GROWTH ; CELL ; Germany ; SITES ; GENE ; GENE-EXPRESSION ; PROTEIN ; transcription ; DRUG ; COMPLEX ; DNA ; MECHANISM ; mechanisms ; CHROMATIN ; gene expression ; DNA-REPAIR ; DNA methylation ; DAMAGE ; METHYLATION ; DNA repair ; FACTOR TIF-IA ; POLYMERASE-I TRANSCRIPTION ; DNA damage ; TECHNOLOGY ; NoRC ; STRAND BREAKS ; STRESS-PROTEIN ; P53-REGULATED PROTEIN GADD45
    Abstract: Many studies have detailed the repressive effects of DNA methylation on gene expression. However, the mechanisms that promote active demethylation are just beginning to emerge. Here, we show that methylation of the rDNA promoter is a dynamic and reversible process. Demethylation of rDNA is initiated by recruitment of Gadd45a (growth arrest and DNA damage inducible protein 45 alpha) to the rDNA promoter by TAR 2, a TBP-associated factor that is contained in Pol I- and Pol II-specific TBP-TAF complexes. Once targeted to rDNA, Gadd45a triggers demethylation of promoter-proximal DNA by recruiting the nucleotide excision repair (NER) machinery to remove methylated cytosines. Knockdown of Gadd45a, XPA, XPG, XPF, or TAR12 or treatment with drugs that inhibit NER causes hypermethylation of rDNA, establishes heterochromatic histone marks, and impairs transcription. The results reveal a mechanism that recruits the DNA repair machinery to the promoter of active genes, keeping them in a hypomethylated state
    Type of Publication: Journal article published
    PubMed ID: 19217408
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  • 6
    Keywords: SURVIVAL ; CELL ; Germany ; MICROSCOPY ; screening ; GENE ; GENES ; GENOME ; RNA ; IDENTIFICATION ; ARRAYS ; HUMAN GENOME ; MIGRATION ; PHENOTYPE ; ORGANIZATION ; INTERFERENCE ; RNA INTERFERENCE ; RESOURCE ; SCIENCE ; LIFE ; TISSUE-CULTURE CELLS
    Abstract: Despite our rapidly growing knowledge about the human genome, we do not know all of the genes required for some of the most basic functions of life. To start to fill this gap we developed a high-throughput phenotypic screening platform combining potent gene silencing by RNA interference, time-lapse microscopy and computational image processing. We carried out a genome-wide phenotypic profiling of each of the similar to 21,000 human protein-coding genes by two-day live imaging of fluorescently labelled chromosomes. Phenotypes were scored quantitatively by computational image processing, which allowed us to identify hundreds of human genes involved in diverse biological functions including cell division, migration and survival. As part of the Mitocheck consortium, this study provides an in-depth analysis of cell division phenotypes and makes the entire high-content data set available as a resource to the community
    Type of Publication: Journal article published
    PubMed ID: 20360735
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  • 7
    Keywords: proliferation ; tumor ; CELL ; Germany ; PATHWAY ; GENE ; PROTEIN ; METABOLISM ; DIFFERENTIATION ; MICE ; KERATINOCYTES ; SKIN ; BIOLOGY ; MUTATION ; MUTATIONS ; BODY ; ORGANIZATION ; CHROMOSOMAL LOCALIZATION ; epidermal barrier ; BARRIER FUNCTION ; TIGHT JUNCTIONS ; TERMINAL DIFFERENTIATION ; MOLECULAR-CLONING ; DEFICIENCY ; RE ; keratinocyte ; development ; IMPAIRMENT ; analysis ; USA ; function ; LOSSES ; congenital ; ATOPIC-DERMATITIS ; GENOMIC STRUCTURE ; - ; ichthyosis ; CAUSE ICHTHYOSIS VULGARIS ; LIPOXYGENASES ; RECESSIVE CONGENITAL ICHTHYOSIS ; WATER-LOSS
    Abstract: 12R-lipoxygenase (12R-LOX) and the epidermal LOX-3 (eLOX-3) constitute a novel LOX pathway involved in terminal differentiation in skin. This view is supported by recent studies showing that inactivating mutations in 12R-LOX and eLOX-3 are linked to the development of autosomal recessive congenital ichthyosis. We show that 12R-LOX deficiency in mice results in a severe impairment of skin barrier function. Loss of barrier function occurs without alterations in proliferation and stratified organization of the keratinocytes, but is associated with ultrastructural anomalies in the upper granular layer, suggesting perturbance of the assembly/extrusion of lamellar bodies. Cornified envelopes from skin of 12R-LOX-deficient mice show increased fragility. Lipid analysis demonstrates a disordered composition of ceramides, in particular a decrease of ester-bound ceramide species. Moreover, processing of profilaggrin to monomeric filaggrin is impaired. This study indicates that the 12R-LOX-eLOX-3 pathway plays a key role in the process of epidermal barrier acquisition by affecting lipid metabolism, as well as protein processing
    Type of Publication: Journal article published
    PubMed ID: 17403930
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  • 8
    Keywords: APOPTOSIS ; EXPRESSION ; CELL ; Germany ; IN-VIVO ; MODEL ; PATHWAY ; VIVO ; SYSTEM ; GENE ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; transcription ; HEART ; MICE ; ACTIVATION ; DNA ; TRANSCRIPTION FACTOR ; BIOLOGY ; ELEMENT-BINDING PROTEIN ; RESPONSE ELEMENT ; TARGETED MUTATION ; TRANSGENIC MICE ; gene expression ; fragmentation ; inactivation ; SIGNALING PATHWAY ; MORPHOLOGY ; FAILURE ; CYCLIC-AMP ; REGULATOR ; Bcl-2 ; CASPASE ; signaling ; GENE-TRANSCRIPTION ; CARDIAC MYOCYTES ; KNOCKOUT MICE ; USA ; function ; caspases ; in vivo ; Cre-loxP system ; NUCLEAR-PROTEIN ; VENTRICULAR FUNCTION ; cAMP responsive element binding protein ; CONGESTIVE-HEART-FAILURE ; SOMATOSTATIN GENE
    Abstract: The transcription factor cAMP response element (CRE)-binding protein (CREB, Creb1) plays a critical role in regulating gene expression in response to activation of the cAMP-dependent signaling pathway, which is implicated in the pathophysiology of heart failure. Using the Cre-loxP system, we generated mice with a cardiomyocyte- specific inactivation of CREB and studied in this model whether CREB is critical for cardiac function. CREB-deficient mice were viable and displayed neither changes in cardiac morphology nor alterations of basal or isoproterenol-stimulated left ventricular function in vivo or of important cardiac regulatory proteins. Since CREB was proposed as a negative regulator of cardiomyocyte apoptosis by enhancing the expression of the antiapoptotic protein Bcl-2, we analyzed the fragmentation of DNA, the activity of caspases 3/7 and the expression of Bcl-2 and did not observe any differences between CREB-deficient and CREB- normal hearts. Our results suggest that the presence of CREB is not critical for normal cardiac function in mice.-Matus M., Lewin G., Stumpel F., Buchwalow I. B., Schneider M. D., Schutz G., Schmitz W., and Muller F. U. Cardiomyocyte-specific inactivation of transcription factor CREB in mice
    Type of Publication: Journal article published
    PubMed ID: 17307839
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  • 9
    Keywords: GROWTH ; Germany ; GENE ; GENES ; RNA ; COMPLEX ; DNA ; PHOSPHORYLATION ; ASSOCIATION ; PROMOTER ; ELEMENTS ; DNA methylation ; METHYLATION ; S-PHASE ; ENHANCEMENT ; POLYMERASE-I TRANSCRIPTION ; LAEVIS ; NoRC ; REMODELING COMPLEX NORC ; rDNA ; non-coding RNA ; epigenetic silencing ; SPACER ; spacer promoter
    Abstract: Epigenetic silencing of a fraction of ribosomal DNA (rDNA) requires association of the nucleolar chromatin-remodelling complex NoRC to 150-250 nucleotide RNAs (pRNA) that originate from an RNA polymerase I promoter located in the intergenic spacer separating rDNA repeats. Here, we show that NoRC-associated pRNA is transcribed from a sub-fraction of hypomethylated rRNA genes during mid S phase, acting in trans to inherit DNA methylation and transcriptional repression of late-replicating silent rDNA copies. The results reveal variability between individual rDNA clusters with distinct functional consequences
    Type of Publication: Journal article published
    PubMed ID: 20010804
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  • 10
    Keywords: EXPRESSION ; proliferation ; SURVIVAL ; CELL ; Germany ; PATHWAY ; GENE ; GENES ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; RESPONSES ; COMPLEXES ; CONTRAST ; ACID ; LYMPHOMA ; PROMOTER ; MUTATION ; inactivation ; REGION ; MUTATIONS ; EXCHANGE ; ONCOGENE ; CENTRAL-NERVOUS-SYSTEM ; NF-kappa B ; pathology ; METHYLATION ; REGULATOR ; CELL LYMPHOMA ; HODGKINS-LYMPHOMA ; coiled coil ; PCNSL ; PROMOTER METHYLATION ; B-CELL ; somatic mutation ; SOMATIC MUTATIONS ; CONTRIBUTE ; NF kappa B ; A20 ; CARD11 ; TNFAIP3
    Abstract: Primary CNS lymphoma (PCNSL), the intracerebral subgroup of diffuse large B cell lymphoma (DLBCL), shows evidence for aberrant activation of the nuclear factor (NF)-kappa B pathway. In order to identify potential activators of the NF-kappa B complex, we analyzed the CARD11 and TNFAIP3 genes for the presence of somatic mutations and TNFAIP3 for aberrant promoter methylation in PCNSL. We also compared PCNSL to spinal DLBCL, because CARD11 and TNFAIP3 mutations have been described in systemic DLBCL. CARD11 mutations, located in the coiled-coil region, which may activate NF-kappa B, were detected in 16% (5/32) of PCNSL, while TNFAIP3 mutations were detected in 3% (1/32) of PCNSL. In PCNSL, all CARD11 mutations were heterozygous, in-frame, induced amino acid exchanges, and presumably led to activation of this oncogene. Spinal DLBCL harbored mutations of CARD11 and TNFAIP3 in 10% (1/10) and 20% (2/10) of cases, respectively. In both PCNSL and spinal DLBCL, mutations in CARD11 and TNFAIP3 were mutually exclusive. TNFAIP3 was unmethylated in all PCNSLs (30/30) and spinal DLBCLs (10/10). We conclude that mutations of the oncogene CARD11 may contribute to NF-kappa B activation and thereby play a role in the pathogenesis of PCNSL, while, in contrast to systemic DLBCL, inactivation of TNFAIP3 either by mutation or methylation seems to be of minor significance
    Type of Publication: Journal article published
    PubMed ID: 20544211
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