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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of biological chemistry, 23 March 2012, Vol.287(13), pp.9672-81
    Description: Stinging cells or nematocytes of jellyfish and other cnidarians represent one of the most poisonous and sophisticated cellular inventions in animal evolution. This ancient cell type is unique in containing a giant secretory vesicle derived from the Golgi apparatus. The organelle structure within the vesicle comprises an elastically stretched capsule (nematocyst) to which a long tubule is attached. During exocytosis, the barbed part of the tubule is accelerated with 〉5 million g in 〈700 ns, enabling a harpoon-like discharge (Nüchter, T., Benoit, M., Engel, U., Ozbek, S., and Holstein, T. W. (2006) Curr. Biol. 16, R316-R318). Hitherto, the molecular components responsible for the organelle's biomechanical properties were largely unknown. Here, we describe the proteome of nematocysts from the freshwater polyp Hydra magnipapillata. Our analysis revealed an unexpectedly complex secretome of 410 proteins with venomous and lytic but also adhesive or fibrous properties. In particular, the insoluble fraction of the nematocyst represents a functional extracellular matrix structure of collagenous and elastic nature. This finding suggests an evolutionary scenario in which exocytic vesicles harboring a venomous secretome assembled a sophisticated predatory structure from extracellular matrix motif proteins.
    Keywords: Evolution, Molecular ; Exocytosis -- Physiology ; Hydra -- Metabolism ; Nematocyst -- Metabolism ; Proteome -- Metabolism ; Secretory Vesicles -- Metabolism
    E-ISSN: 1083-351X
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  • 2
    In: Nature, 2011, Vol.471(7340), p.591
    Description: Members of the tumour necrosis factor (TNF) receptor superfamily have important functions in immunity and inflammation. Recently linear ubiquitin chains assembled by a complex containing HOIL-1 and HOIP (also known as RBCK1 and RNF31, respectively) were implicated in TNF signalling, yet their relevance in vivo remained uncertain. Here we identify SHARPIN as a third component of the linear ubiquitin chain assembly complex, recruited to the CD40 and TNF receptor signalling complexes together with its other constituents, HOIL-1 and HOIP. Mass spectrometry of TNF signalling complexes revealed RIP1 (also known as RIPK1) and NEMO (also known as IKKγ or IKBKG) to be linearly ubiquitinated. Mutation of the Sharpin gene (Sharpin^sup cpdm/cpdm^) causes chronic proliferative dermatitis (cpdm) characterized by inflammatory skin lesions and defective lymphoid organogenesis. Gene induction by TNF, CD40 ligand and interleukin-1β was attenuated in cpdm-derived cells which were rendered sensitive to TNF-induced death. Importantly, Tnf gene deficiency prevented skin lesions in cpdm mice. We conclude that by enabling linear ubiquitination in the TNF receptor signalling complex, SHARPIN interferes with TNF-induced cell death and, thereby, prevents inflammation. Our results provide evidence for the relevance of linear ubiquitination in vivo in preventing inflammation and regulating immune signalling. [PUBLICATION ]
    Keywords: Animals–Metabolism ; Cd40 Ligand–Chemistry ; Carrier Proteins–Metabolism ; Carrier Proteins–Metabolism ; Cell Line–Immunology ; Humans–Metabolism ; I-Kappa B Kinase–Pathology ; Immunity–Prevention & Control ; Inflammation–Metabolism ; Inflammation–Chemistry ; Inflammation–Metabolism ; Interleukin-1beta–Metabolism ; Mice–Chemistry ; Multiprotein Complexes–Genetics ; Multiprotein Complexes–Metabolism ; Nf-Kappa B–Metabolism ; Nerve Tissue Proteins–Deficiency ; Nerve Tissue Proteins–Genetics ; Nerve Tissue Proteins–Metabolism ; Phenotype–Cytology ; Receptor-Interacting Protein Serine-Threonine Kinases–Immunology ; Receptors, Tumor Necrosis Factor–Metabolism ; Receptors, Tumor Necrosis Factor–Pathology ; Receptors, Tumor Necrosis Factor–Deficiency ; Signal Transduction–Genetics ; Skin–Chemistry ; Skin–Metabolism ; Skin–Chemistry ; Skin–Metabolism ; Tumor Necrosis Factor-Alpha–Chemistry ; Tumor Necrosis Factor-Alpha–Metabolism ; Ubiquitin–Metabolism ; Ubiquitin–Metabolism ; Ubiquitin-Protein Ligase Complexes–Metabolism ; Ubiquitin-Protein Ligase Complexes–Metabolism ; Ubiquitin-Protein Ligases–Metabolism ; Ubiquitin-Protein Ligases–Metabolism ; Ubiquitination–Metabolism ; Mutation ; Apoptosis ; Proteins ; Recruitment ; Disease ; Carrier Proteins ; Ikbkg Protein, Human ; Interleukin-1beta ; Multiprotein Complexes ; Nf-Kappa B ; Nerve Tissue Proteins ; Rnf31 Protein, Human ; Receptors, Tumor Necrosis Factor ; Tumor Necrosis Factor-Alpha ; Ubiquitin ; Sharpin ; Cd40 Ligand ; Ripk1 Protein, Human ; Receptor-Interacting Protein Serine-Threonine Kinases ; I-Kappa B Kinase ; Hoil-1 Protein, Human ; Ubiquitin-Protein Ligase Complexes ; Ubiquitin-Protein Ligases;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
    Language: English
    In: 2012, Vol.7(9), p.e45682
    Description: Tardigrades have fascinated researchers for more than 300 years because of their extraordinary capability to undergo cryptobiosis and survive extreme environmental conditions. However, the survival mechanisms of tardigrades are still poorly understood mainly due to the absence of detailed knowledge about the proteome and genome of these organisms. Our study was intended to provide a basis for the functional characterization of expressed proteins in different states of tardigrades. High-throughput, high-accuracy proteomics in combination with a newly developed tardigrade specific protein database resulted in the identification of more than 3000 proteins in three different states: early embryonic state and adult animals in active and anhydrobiotic state. This comprehensive proteome resource includes protein families such as chaperones, antioxidants, ribosomal proteins, cytoskeletal proteins, transporters, protein channels, nutrient reservoirs, and developmental proteins. A comparative analysis of protein families in the different states was performed by calculating the exponentially modified protein abundance index which classifies proteins in major and minor components. This is the first step to analyzing the proteins involved in early embryonic development, and furthermore proteins which might play an important role in the transition into the anhydrobiotic state.
    Keywords: Research Article ; Biology ; Biochemistry
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: PLoS ONE, 2010, Vol.5(3), p.e9502
    Description: Tardigrades are small, multicellular invertebrates which are able to survive times of unfavourable environmental conditions using their well-known capability to undergo cryptobiosis at any stage of their life cycle. Milnesium tardigradum has become a powerful model system for the analysis of cryptobiosis. While some genetic information is already available for Milnesium tardigradum the proteome is still to be discovered. ; Here we present to the best of our knowledge the first comprehensive study of on the protein level. To establish a proteome reference map we developed optimized protocols for protein extraction from tardigrades in the active state and for separation of proteins by high resolution two-dimensional gel electrophoresis. Since only limited sequence information of on the genome and gene expression level is available to date in public databases we initiated in parallel a tardigrade EST sequencing project to allow for protein identification by electrospray ionization tandem mass spectrometry. 271 out of 606 analyzed protein spots could be identified by searching against the publicly available NCBInr database as well as our newly established tardigrade protein database corresponding to 144 unique proteins. Another 150 spots could be identified in the tardigrade clustered EST database corresponding to 36 unique contigs and ESTs. Proteins with annotated function were further categorized in more detail by their molecular function, biological process and cellular component. For the proteins of unknown function more information could be obtained by performing a protein domain annotation analysis. Our results include proteins like protein member of different heat shock protein families and LEA group 3, which might play important roles in surviving extreme conditions. ; The proteome reference map of provides the basis for further studies in order to identify and characterize the biochemical mechanisms of tolerance to extreme desiccation. The optimized proteomics workflow will enable application of sensitive quantification techniques to detect differences in protein expression, which are characteristic of the active and anhydrobiotic states of tardigrades.
    Keywords: Research Article ; Biochemistry -- Protein Chemistry ; Biotechnology -- Protein Chemistry And Proteomics ; Chemical Biology -- Protein Chemistry And Proteomics
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: The Journal of clinical investigation, June 2010, Vol.120(6), pp.2230-42
    Description: Identifying the antigens that have the potential to trigger endogenous antitumor responses in an individual cancer patient is likely to enhance the efficacy of cancer immunotherapy, but current methodologies do not efficiently identify such antigens. This study describes what we believe to be a new method of comprehensively identifying candidate tissue antigens that spontaneously cause T cell responses in disease situations. We used the newly developed automated, two-dimensional chromatography system PF2D to fractionate the proteome of human tumor tissues and tested protein fractions for recognition by preexisting tumor-specific CD4+ Th cells and CTLs. Applying this method using mice transgenic for a TCR that recognizes an OVA peptide presented by MHC class I, we demonstrated efficient separation, processing, and cross-presentation to CD8+ T cells by DCs of OVA expressed by the OVA-transfected mouse lymphoma RMA-OVA. Applying this method to human tumor tissues, we identified MUC1 and EGFR as tumor-associated antigens selectively recognized by T cells in patients with head and neck cancer. Finally, in an exemplary patient with a malignant brain tumor, we detected CD4+ and CD8+ T cell responses against two novel antigens, transthyretin and calgranulin B/S100A9, which were expressed in tumor and endothelial cells. The immunogenicity of these antigens was confirmed in 4 of 10 other brain tumor patients. This fast and inexpensive method therefore appears suitable for identifying candidate T cell antigens in various disease situations, such as autoimmune and malignant diseases, without being restricted to expression by a certain cell type or HLA allele.
    Keywords: Antigens, Neoplasm -- Chemistry ; Peptides -- Chemistry ; T-Lymphocytes -- Immunology
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 6
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 January 2012, Vol.18(1), pp.105-17
    Description: Recent work points out a role of B7H3, a member of the B7-family of costimulatory proteins, in conveying immunosuppression and enforced invasiveness in a variety of tumor entities. Glioblastoma is armed with effective immunosuppressive properties resulting in an impaired recognition and ineffective attack of tumor cells by the immune system. In addition, extensive and diffuse invasion of tumor cells into the surrounding brain tissue limits the efficacy of local therapies. Here, 4IgB7H3 is assessed as diagnostic and therapeutic target for glioblastoma. To characterize B7H3 in glioblastoma, we conduct analyses not only in glioma cell lines and glioma-initiating cells but also in human glioma tissue specimens. B7H3 expression by tumor and endothelial cells correlates with the grade of malignancy in gliomas and with poor survival. Both soluble 4IgB7H3 in the supernatant of glioma cells and cell-bound 4IgB7H3 are functional and suppress natural killer cell-mediated tumor cell lysis. Gene silencing showed that membrane and soluble 4IgB7H3 convey a proinvasive phenotype in glioma cells and glioma-initiating cells in vitro. These proinvasive and immunosuppressive properties were confirmed in vivo by xenografted 4IgB7H3 gene silenced glioma-initiating cells, which invaded significantly less into the surrounding brain tissue in an orthotopic model and by subcutaneously injected LN-229 cells, which were more susceptible to natural killer cell-mediated cytotoxicity than unsilenced control cells. Because of its immunosuppressive and proinvasive function, 4IgB7H3 may serve as a therapeutic target in the treatment of glioblastoma.
    Keywords: B7 Antigens -- Metabolism ; Cell Movement -- Immunology ; Cytotoxicity, Immunologic -- Immunology ; Glioblastoma -- Immunology ; Killer Cells, Natural -- Immunology
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 7
    Language: English
    In: Biogerontology, 2010, Vol.11(3), pp.321-334
    Description: Mitochondria being the major source and target of reactive oxygen species (ROS) play a crucial role during ageing. We analyzed ageing and calorie restriction (CR)-induced changes in abundance of rat liver mitochondrial proteins to understand key aspects behind the age-retarding mechanism of CR. The combination of blue-native (BN) gel system with fluorescence Difference Gel Electrophoresis (DIGE) facilitated an efficient analysis of soluble and membrane proteins, existing as monomers or multi-protein assemblies. Changes in abundance of specific key subunits of respiratory chain complexes I, IV and V, critical for activity and/or assembly of the complexes were identified. CR lowered complex I assembly and complex IV activity, which is discussed as a molecular mechanism to minimize ROS production at mitochondria. Notably, the antioxidant system was found to be least affected. The GSH:GSSG couple could be depicted as a rapid mean to handle the fluctuations in ROS levels led by reversible metabolic shifts. We evaluated the relative significance of ROS generation against quenching. We also observed parallel and unidirectional changes as effect of ageing and CR, in subunits of ATP synthase, cytochrome P450 and glutathione S-transferase. This is the first report on such ‘putatively hormetic’ ageing-analogous effects of CR, besides the age-retarding ones.
    Keywords: Ageing ; Antioxidants ; Calorie restriction ; DIGE ; Proteomics ; Mitochondria
    ISSN: 1389-5729
    E-ISSN: 1573-6768
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  • 8
    Language: English
    In: Molecular biology and evolution, August 2015, Vol.32(8), pp.1928-47
    Description: The cnidarian freshwater polyp Hydra sp. exhibits an unparalleled regeneration capacity in the animal kingdom. Using an integrative transcriptomic and stable isotope labeling by amino acids in cell culture proteomic/phosphoproteomic approach, we studied stem cell-based regeneration in Hydra polyps. As major contributors to head regeneration, we identified diverse signaling pathways adopted for the regeneration response as well as enriched novel genes. Our global analysis reveals two distinct molecular cascades: an early injury response and a subsequent, signaling driven patterning of the regenerating tissue. A key factor of the initial injury response is a general stabilization of proteins and a net upregulation of transcripts, which is followed by a subsequent activation cascade of signaling molecules including Wnts and transforming growth factor (TGF) beta-related factors. We observed moderate overlap between the factors contributing to proteomic and transcriptomic responses suggesting a decoupled regulation between the transcriptional and translational levels. Our data also indicate that interstitial stem cells and their derivatives (e.g., neurons) have no major role in Hydra head regeneration. Remarkably, we found an enrichment of evolutionarily more recent genes in the early regeneration response, whereas conserved genes are more enriched in the late phase. In addition, genes specific to the early injury response were enriched in transposon insertions. Genetic dynamicity and taxon-specific factors might therefore play a hitherto underestimated role in Hydra regeneration.
    Keywords: Cnidaria ; Hydra ; Evolution of Regeneration ; Proteomics and Transcriptomics ; Gene Expression Regulation -- Physiology ; Hydra -- Physiology ; Regeneration -- Physiology ; Transcriptome -- Physiology ; Wnt Signaling Pathway -- Physiology
    ISSN: 07374038
    E-ISSN: 1537-1719
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  • 9
    In: Hepatology, November 2018, Vol.68(5), pp.1817-1832
    Description: The identification of viability‐associated long noncoding RNAs (lncRNAs) might be a promising rationale for new therapeutic approaches in liver cancer. Here, we applied an RNA interference screening approach in hepatocellular carcinoma (HCC) cell lines to find viability‐associated lncRNAs. Among the multiple identified lncRNAs with a significant impact on HCC cell viability, we selected cancer susceptibility 9 (CASC9) due to the strength of its phenotype, expression, and up‐regulation in HCC versus normal liver. CASC9 regulated viability across multiple HCC cell lines as shown by clustered regularly interspaced short palindromic repeats interference and single small interfering RNA (siRNA)–mediated and siRNA pool–mediated depletion of CASC9. Further, CASC9 depletion caused an increase in apoptosis and a decrease of proliferation. We identified the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL) as a CASC9 interacting protein by RNA affinity purification and validated it by native RNA immunoprecipitation. Knockdown of HNRNPL mimicked the loss‐of‐viability phenotype observed upon CASC9 depletion. Analysis of the proteome (stable isotope labeling with amino acids in cell culture) of CASC9‐depleted and HNRNPL‐depleted cells revealed a set of coregulated genes which implied a role of the CASC9:HNRNPL complex in AKT signaling and DNA damage sensing. CASC9 expression levels were elevated in patient‐derived tumor samples compared to normal control tissue and had a significant association with overall survival of HCC patients. In a xenograft chicken chorioallantoic membrane model, we measured decreased tumor size after knockdown of CASC9. Taken together, we provide a comprehensive list of viability‐associated lncRNAs in HCC; we identified the CASC9:HNRNPL complex as a clinically relevant viability‐associated lncRNA/protein complex which affects AKT signaling and DNA damage sensing in HCC.
    Keywords: Chorioallantoic Membrane ; RNA-Mediated Interference ; Hepatocellular Carcinoma ; L Form ; Crispr ; Liver Cancer ; Apoptosis ; Cell Culture ; RNA-Binding Protein ; Immunoprecipitation ; DNA Damage ; Phenotypes ; Protein Purification ; DNA Damage ; Cell Lines ; Sirna ; Tumor Cell Lines ; Liver Cancer ; Akt Protein ; Xenografts ; Proteins;
    ISSN: 0270-9139
    E-ISSN: 1527-3350
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  • 10
    Language: English
    In: Neurogenetics, December 2018, Vol.19(4), pp.237-255
    Description: Autosomal recessive ataxia telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency, and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the ataxia telangiectasiamutated (ATM) gene, a serine-threonine protein kinase involved in DNA damage response and excitatory neurotransmission. The selective vulnerability of cerebellar Purkinje neurons (PN) to A-T is not well understood. Employing global proteomic profiling of cerebrospinal fluid from patients at ages around 15 years, we detected reduced calbindin, reelin, cerebellin-1, cerebellin-3, protocadherin fat 2, sempahorin 7A, and increased apolipoprotein B and J peptides. Bioinformatic enrichment was observed for pathways of lipoproteins, endocytosis, extracellular matrix receptor interaction, peptidase activity, adhesion, calcium binding, and complement immunity. This seemed important since secretion of reelin from glutamatergic afferent axons is crucial for PN lipoprotein receptor endocytosis and lipid signaling. Reelin expression is downregulated by irradiation and reelin/ApoB mutations are known causes of ataxia. Validation efforts in 2-month-old Atm-/- mice before onset of motor deficits confirmed cerebellar transcript reductions for reelin receptors Apoer2/Vldlr with increases for their ligands Apoe/Apoh and cholesterol 24-hydroxylase Cyp46a1. Concomitant dysregulations were found for Vglut2/Sema7a as climbing fiber markers, glutamate receptors like Grin2b, and calcium homeostasis factors (Atp2b2, Calb1, Itpr1), while factors involved in DNA damage, oxidative stress, neuroinflammation, and cell adhesion were normal at this stage. Quantitative immunoblots confirmed ApoB and ApoJ increases and VLDLR reduction in cerebellar tissue at the age of 2 months. These findings show that ApoB excess and reelin signaling deficits reflect the neurodegeneration in A-T in a sensitive and specific way. As extracellular factors, apolipoproteins and their cargo such as vitamin E may be useful for neuroprotective interventions.
    Keywords: Apob ; Ataxia Telangiectasia ; Diagnostic Biomarkers ; Label-Free Mass Spectrometry ; Reelin ; Apolipoproteins B ; Cell Adhesion Molecules, Neuronal ; Extracellular Matrix Proteins ; Nerve Tissue Proteins ; Serine Endopeptidases ; Ataxia Telangiectasia -- Genetics
    ISSN: 13646745
    E-ISSN: 1364-6753
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