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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of biological chemistry, 19 June 2015, Vol.290(25), pp.15758-69
    Description: The cysteine protease cathepsin L (CTSL) is often thought to act as a tumor promoter by enhancing tumor progression and metastasis. This goes along with increased CTSL activity in various tumor entities; however, the mechanisms leading to high CTSL levels are incompletely understood. With the help of the polyoma middle T oncogene driven breast cancer mouse model expressing a human CTSL genomic transgene, we show that CTSL indeed promotes breast cancer metastasis to the lung. During tumor formation and progression high expression levels of CTSL are maintained by enduring translation of CTSL mRNA. Interestingly, human breast cancer specimens expressed the same pattern of 5' untranslated region (UTR) splice variants as the transgenic mice and the human cancer cell line MDA-MB 321. By polyribosome profiling of tumor tissues and human breast cancer cells, we observe an intrinsic resistance of CTSL to stress-induced shutdown of translation. This ability can be attributed to all 5' UTR variants of CTSL and is not dependent on a previously described internal ribosomal entry site motif. In conclusion, we provide in vivo functional evidence for overexpressed CTSL as a promoter of lung metastasis, whereas high CTSL levels are maintained during tumor progression due to stress-resistant mRNA translation.
    Keywords: Alternative Splicing ; Breast Cancer ; Cysteine Protease ; Metastasis ; Translation Control ; 5' Untranslated Regions ; Protein Biosynthesis ; Stress, Physiological ; Breast Neoplasms -- Metabolism ; Cathepsin L -- Biosynthesis ; Lung Neoplasms -- Metabolism ; Mammary Neoplasms, Experimental -- Metabolism ; RNA, Neoplasm -- Metabolism
    E-ISSN: 1083-351X
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  • 2
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 01 June 2012, Vol.188(11), pp.5438-47
    Description: Dipeptidylpeptidase IV (CD26) is a multifunctional ectoenzyme involved in T cell activation that has been implicated in autoimmune pathophysiology. Because IL-17-producing CD4(+) T cells (Th17 cells) are important mediators of autoimmune disease, we analyzed the expression of CD26 and its enzymatic function on human Th17 cells. Analysis of CD26 expression on different CD4(+) T helper subsets showed that CD26 expression is highest on CD4(+) T cells producing type 17 cytokines (e.g., IL-22, IL-17, GM-CSF, or TNF) compared with Th1, Th2, and regulatory T cells. Phenotypic analysis revealed that CD26(++)CD4(+) T cells express the type 17 differentiation molecules CD161, CCR6, lL-23R, and retinoic acid-related orphan receptor-γt. Furthermore, sorted CD26(++)CD4(+) T cells contain 〉90-98% of Th17 cells, indicating that CD26(++) T cells harbor the Th17 lineage. A comparison with CD161 and CCR6 indicated that analysis of CD26 coexpression may improve the phenotypic characterization of Th17 cells. Of note, CD26(++) Th17 cells are enriched in the inflamed tissue of patients with hepatitis and inflammatory bowel disease. Functional analysis in migration assays revealed that CD26 expressed on Th17 cells is enzymatically active. Indeed, CD26 negatively regulates the chemotactic CD4(+) T cell response to the inflammatory chemokines CXCL9-12 that can be restored by pharmacological blockade of the enzymatic center of CD26. In summary, these results strongly suggest that CD26 may contribute to the orchestration of the immune response by Th17 cells in human inflammatory diseases. They also suggest that the phenotypic analysis of Th17 cells may be facilitated by determination of CD26 expression.
    Keywords: Dipeptidyl Peptidase 4 -- Biosynthesis ; Th17 Cells -- Enzymology ; Up-Regulation -- Immunology
    ISSN: 00221767
    E-ISSN: 1550-6606
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 3
    Language: English
    In: Cytokine, November 2015, Vol.76(1), pp.105-105
    Description: The pattern recognition receptor RIG-I is a pivotal sensor of viral infections. Its activation by 5′-triphosphorylated- or double-stranded-RNA leads to subsequent signaling via MAVS, TBK1 and IKK epsilon resulting in IRF3 nuclear translocation. Activated IRF3 induces transcription of type I and type III interferons and several interferon stimulated genes. Despite intensive investigations on the RIG-I signaling pathway, its regulatory network still remains largely elusive.To gain more insight into the complex regulation of this pathway a kinome-wide siRNA screen was performed. The primary screen revealed over 100 siRNAs that significantly altered the translocation of IRF3 to the nucleus upon RIG-I stimulation. The top 50 candidates were further analyzed in three independent validation screens based on IRF3-sensitive promoter reporter assays or Rift-valley-fever virus replication. Taking all three validation screens into account, 21 novel regulators of the RIG-I signaling pathway could be identified. Relevance of the identified hits in regulating the host-cell antiviral defense was demonstrated by analyzing cytokine profiles and the impact on Influenza A virus replication.In the course of this screen, DAPK1 was identified as an inhibitor of RIG-I mediated IRF3 activation. Extensive mapping experiments revealed a minimal construct, including the kinase domain, to be sufficient for inhibiting IRF3 reporter activation in over-expression experiments. Furthermore, interaction studies revealed binding of DAPK1 to ligand-activated RIG-I, suggesting that a DAPK1 mediated phosphorylation of RIG-I inhibits its activity. In fact, in an in vitro kinase assays we could demonstrate that RIG-I is a substrate of DAPK1.
    Keywords: Medicine ; Biology
    ISSN: 1043-4666
    E-ISSN: 1096-0023
    Source: ScienceDirect Journals (Elsevier)
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  • 4
    Language: English
    In: Cytokine, 11/2015, Vol.76(1), p.105
    ISSN: 10434666
    Source: Elsevier (via CrossRef)
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  • 5
    Language: English
    In: Molecular Cell, 02 February 2017, Vol.65(3), pp.403-415.e8
    Description: Cell-autonomous induction of type I interferon must be stringently regulated. Rapid induction is key to control virus infection, whereas proper limitation of signaling is essential to prevent immunopathology and autoimmune disease. Using unbiased kinome-wide RNAi screening followed by thorough validation, we identified 22 factors that regulate RIG-I/IRF3 signaling activity. We describe a negative-feedback mechanism targeting RIG-I activity, which is mediated by death associated protein kinase 1 (DAPK1). RIG-I signaling triggers DAPK1 kinase activation, and active DAPK1 potently inhibits RIG-I stimulated IRF3 activity and interferon-beta production. DAPK1 phosphorylates RIG-I in vitro at previously reported as well as other sites that limit 5′ppp-dsRNA sensing and virtually abrogate RIG-I activation. Willemsen et al. screened the antiviral RIG-I pathway for regulators and identified and validated 22 kinases. They describe an inhibitory feedback loop mediated by DAPK1. Antiviral signaling activates DAPK1 kinase activity, which, in turn, inactivates RIG-I by direct phosphorylation.
    Keywords: Innate Immunity ; Antiviral Response ; Pattern Recognition Receptors ; Signal Transduction ; Feedback Regulation ; Interferon System ; Cytokines ; Dapk1 ; Rig-I ; Ddx58 ; Biology
    ISSN: 1097-2765
    E-ISSN: 1097-4164
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  • 6
    Text Resource
    Text Resource
    Heidelberg University Library
    Keywords: Natural Sciences And Mathematics
    Source: DataCite
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