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  • 1
    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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  • 2
    Keywords: CANCER ; EXPRESSION ; tumor ; carcinoma ; Germany ; human ; LUNG ; GENE ; GENE-EXPRESSION ; HYBRIDIZATION ; PROTEIN ; MONOCLONAL-ANTIBODY ; TISSUE ; TUMORS ; kidney ; TISSUES ; BREAST-CANCER ; antibodies ; antibody ; STAGE ; IN-SITU ; PROGRESSION ; ARRAYS ; metastases ; HETEROZYGOSITY ; REGION ; MONOCLONAL-ANTIBODIES ; CARCINOMAS ; NORMAL TISSUE ; HISTONE ACETYLTRANSFERASE ; ovarian carcinoma ; METHYLATION ; MITOSIS ; DEFICIENCY ; ONCOLOGY ; pancreas ; RE ; PATTERN ; ARRAY ; mRNA ; MALIGNANT PROGRESSION ; biomarker ; monoclonal antibodies ; EPITHELIAL TUMORS ; USA ; LOSSES ; MAMMARY-CARCINOMA ; SET ; NOV ; cDNA array ; NUCLEAR-MEMBRANE ; epigenetic regulation ; hMOF ; RECESSIVE CEREBELLAR-ATAXIA ; SYNE-1
    Abstract: In a study on gene deregulation in ovarian carcinoma we found a mRNA ceding for a 350 kDa protein, Drop1, to be downregulated 20- to 180-fold in the majority of ovarian and mammary carcinomas. The mRNA is encoded by a set of exons in the 5' region of the SYNE1 gene. Immunohistochemical staining for Drop1 protein by a specific monoclonal antibody corresponds to the pattern seen for the mRNA. cDNA arrays of matched pairs of tumor and normal tissue and in situ hybridizations confirmed the drastic loss of Drop1 mRNA as a common feature in uterus, cervix, kidney, lung, thyroid and pancreas carcinomas, already at early tumor stages and in all metastases. Two-hybrid studies suggest a role of this deficiency in the malignant progression of epithelial tumors. (c) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18709643
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  • 3
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; DEATH ; POPULATION ; TISSUE ; MACROPHAGES ; MARKER ; RECOGNITION ; MOUSE ; prevention ; PHAGOCYTOSIS ; MARKERS ; DAMAGE ; NETHERLANDS ; CLEARANCE ; CENTRAL-NERVOUS-SYSTEM ; RECEPTORS ; microglia ; MULTIPLE-SCLEROSIS ; mannose receptor ; SUBPOPULATION ; RE ; BRAIN-TUMORS ; GLIOMA ; GLIOMA-CELLS ; FUNCTIONAL-CHARACTERIZATION ; cell death ; APOPTOTIC CELLS ; immunology ; STRAIN
    Abstract: Microglia phagocytic activity for apoptotic glioma cells is hardly analysed inspite of its relevance to tissue damage prevention. We provide evidence for a phosphatidyl serine-independent clearance of mouse glioma cells at an advanced stage of death, suggesting microglia recognition of late apoptotic markers. Dying cells were immediately cleared or stayed for hours in that stage before engulfment occurred. This phagocytic activity was restricted to a microglia subset representing 30 to 70% of the population according to the used strain. Expression of receptors involved in late apoptotic markers recognition therefore seems confined to a subpopulation of microglia and to be strain-dependent. (C) 2008 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18495256
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  • 4
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; AGENTS ; CELL ; PATHWAY ; DISEASE ; DISEASES ; PROTEIN ; CULTURED-CELLS ; ACCUMULATION ; RELEASE ; GLYCOPROTEIN ; ISOFORM ; MOUSE ; UP-REGULATION ; PLASMA ; MEMBRANE ; PLASMA-MEMBRANE ; CELL-SURFACE ; protease ; cysteine ; ageing ; CATHEPSIN-B ; CONFORMATIONAL-CHANGES ; CASPASE ; CONFORMATIONAL-CHANGE ; CREUTZFELDT-JAKOB-DISEASE ; INHIBITORS ; PRION PROTEIN ; PRP ACCUMULATION
    Abstract: Prion diseases are characterized by the accumulation of an abnormal, proteinase K-resistant isoform of the prion protein, PrPSc, which is generated by a post-translational conversion of the protease-sensitive normal cell-surface glycoprotein PrPc involving major conformational changes. The conversion is thought to occur at the plasma membrane or along the endocytic pathway towards the lysosome. PrPSc aggregates have been found to accumulate in secondary lysosomes. In our study, the activities of two major lysosomal cysteine proteases, cathepsins B and L, were found to be significantly increased in scrapie-infected Neuro2a cells compared with uninfected cells using biochemical and cytochemical methods. We hypothesize that lysosomal proteases may be involved in a 'second autocatalytic loop' of PrPSc formation, acting in concert with the well-known autocatalytic enhancement of PrP conversion in the presence of PrPSc
    Type of Publication: Journal article published
    PubMed ID: 12867662
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  • 5
    Keywords: EXPRESSION ; DNA ; REPAIR ; MAMMALIAN-CELLS ; REPLICATION ; GREEN FLUORESCENT PROTEIN ; HOMOLOGOUS RECOMBINATION ; DOUBLE-STRAND BREAKS ; MUTANTS ; RED FLUORESCENCE
    Abstract: Several GFP variants have been developedfor multicolor labeling in vivo. Here we report that simultaneous co-transfection of fluorescent protein chimeras can give false-positive results caused by the conversion of spectral properties. Under standard transfection conditions, approximately 8% of cells produce false-positive results, but, depending on the conditions, up to 26% of the cells permanently express altered fusion proteins. This compromises the interpretation of the results. The conversion is independent of transfection methods or cell types. Our results show that the effect is based on homologous recombination/repair/replication process events that occur between the nucleotide sequences of the fluorescent proteins. Consecutive transfection or low sequence similarities avoided recombination. The appearance of conversion facilitates exchanges of spectral properties infusion proteins, the creation of libraries, or the assembly of DNA fusion constructs in vivo. The detailed quantification of the conversion rate allows the investigation of recombination/repair/replication processes in general.
    Type of Publication: Journal article published
    PubMed ID: 11962606
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