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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 27 October 2015, Vol.112(43), pp.E5825-33
    Description: Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFα- and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IκB member IκB (inhibitor of NF-κB) ζ, a selective coactivator of particular NF-κB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IκBζ was identified as a direct transcriptional activator of TNFα/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IκBζ-deficient mice, whereas skin inflammation was still inducible in IL-17A- and TNFα-deficient mice. IκBζ deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IκBζ function by intradermal injection of IκBζ siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IκBζ as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IκBζ could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials.
    Keywords: Iκbζ ; Cytokines ; Inflammation ; Psoriasis ; I-Kappa B Proteins -- Physiology ; Psoriasis -- Physiopathology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 02 October 2018, Vol.115(40), pp.10088-10093
    Description: Proinflammatory cytokine signaling in keratinocytes plays a crucial role in the pathogenesis of psoriasis, a skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although IL-17A and TNFα are effective therapeutic targets in psoriasis, IL-36 has recently emerged as a proinflammatory cytokine. However, little is known about IL-36 signaling and its downstream transcriptional responses. Here, we found that exposure of keratinocytes to IL-36 induced the expression of IκBζ, an atypical IκB member and a specific transcriptional regulator of selective NF-κB target genes. Induction of IκBζ by IL-36 was mediated by NF-κB and STAT3. In agreement, IL-36-mediated induction of IκBζ was found to be required for the expression of various psoriasis-related genes involved in inflammatory signaling, neutrophil chemotaxis, and leukocyte activation. Importantly, IκBζ-knockout mice were protected against IL-36-mediated dermatitis, accompanied by reduced proinflammatory gene expression, decreased immune cell infiltration, and a lack of keratinocyte hyperproliferation. Moreover, expression of IκBζ mRNA was highly up-regulated in biopsies of psoriasis patients where it coincided with levels. Thus our results uncover an important role for IκBζ in IL-36 signaling and validate IκBζ as an attractive target for psoriasis therapy.
    Keywords: Il-36 ; Iκbζ ; Nfkbiz ; Keratinocytes ; Psoriasis ; Cell Proliferation ; Gene Expression Regulation ; Signal Transduction ; Adaptor Proteins, Signal Transducing -- Metabolism ; Interleukin-1 -- Metabolism ; Nuclear Proteins -- Metabolism ; Psoriasis -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    In: The American Journal of Gastroenterology, 2014, Vol.109(1), p.140
    Keywords: Fatty Liver -- Diagnosis ; Keratin-18 -- Blood;
    ISSN: 0002-9270
    E-ISSN: 15720241
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  • 5
    Language: English
    In: The Journal of biological chemistry, 21 January 2011, Vol.286(3), pp.1976-86
    Description: Protein arginine methylation plays a critical role in differential gene expression through modulating protein-protein and protein-DNA/RNA interactions. Although numerous proteins undergo arginine methylation, only limited information is available on how protein arginine methyltransferases (PRMTs) identify their substrates. The human PRMT5 complex consists of PRMT5, WD45/MEP50 (WD repeat domain 45/methylosome protein 50), and pICln and catalyzes the symmetrical arginine dimethylation of its substrate proteins. pICln recruits the spliceosomal Sm proteins to the PRMT5 complex for methylation, which allows their subsequent loading onto snRNA to form small nuclear ribonucleoproteins. To understand how the PRMT5 complex is regulated, we investigated its biochemical composition and identified RioK1 as a novel, stoichiometric component of the PRMT5 complex. We show that RioK1 and pICln bind to PRMT5 in a mutually exclusive fashion. This results in a PRMT5-WD45/MEP50 core structure that either associates with pICln or RioK1 in distinct complexes. Furthermore, we show that RioK1 functions in analogy to pICln as an adapter protein by recruiting the RNA-binding protein nucleolin to the PRMT5 complex for its symmetrical methylation. The exclusive interaction of PRMT5 with either pICln or RioK1 thus provides the first mechanistic insight into how a methyltransferase can distinguish between its substrate proteins.
    Keywords: Ion Channels -- Metabolism ; Multienzyme Complexes -- Metabolism ; Protein Methyltransferases -- Metabolism ; Protein-Serine-Threonine Kinases -- Metabolism
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 6
    Language: English
    In: The Journal of biological chemistry, 10 June 2016, Vol.291(24), pp.12851-61
    Description: Macrophages constitute a first line of pathogen defense by triggering a number of inflammatory responses and the secretion of various pro-inflammatory cytokines. Recently, we and others found that IκBζ, an atypical IκB family member and transcriptional coactivator of selected NF-κB target genes, is essential for macrophage expression of a subset of pro-inflammatory cytokines, such as IL-6, IL-12, and CCL2. Despite defective pro-inflammatory cytokine expression, however, IκBζ-deficient mice develop symptoms of chronic inflammation. To elucidate this discrepancy, we analyzed a regulatory role of IκBζ for the expression of anti-inflammatory cytokines and identified IκBζ as an essential activator of IL-10 expression. LPS-challenged peritoneal and bone marrow-derived macrophages from IκBζ-deficient mice revealed strongly decreased transcription and secretion of IL-10 compared with wild-type mice. Moreover, ectopic expression of IκBζ was sufficient to stimulate Il10 transcription. On the molecular level, IκBζ directly activated the Il10 promoter at a proximal κB site and was required for the transcription-enhancing trimethylation of histone 3 at lysine 4. Together, our findings show for the first time the IκBζ-dependent expression of an anti-inflammatory cytokine that is crucial in controlling immune responses.
    Keywords: Nf-Κb ; Nf-Κb Transcription Factor ; Immunosuppressor ; Interleukin ; Macrophage ; Adaptor Proteins, Signal Transducing -- Metabolism ; Interleukin-10 -- Metabolism ; Macrophages -- Metabolism ; Nf-Kappa B -- Metabolism ; Nuclear Proteins -- Metabolism
    E-ISSN: 1083-351X
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  • 7
    Language: English
    In: The Journal of biological chemistry, 21 April 2017, Vol.292(16), pp.6478-6492
    Description: Renal cell carcinoma (RCC) is polyresistant to chemo- and radiotherapy and biologicals, including TNF-related apoptosis-inducing ligand (TRAIL). Sorafenib, a multikinase inhibitor approved for the treatment of RCC, has been shown to sensitize cancer cells to TRAIL-induced apoptosis, in particular by down-regulation of the Bak-inhibitory Bcl-2 family protein Mcl-1. Here we demonstrate that sorafenib overcomes TRAIL resistance in RCC by a mechanism that does not rely on Mcl-1 down-regulation. Instead, sorafenib induces rapid dissipation of the mitochondrial membrane potential (ΔΨ) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of ΔΨ and ROS production induced by sorafenib are independent of caspase activities and do not depend on the presence of the proapoptotic Bcl-2 family proteins Bax or Bak, indicating that both events are functionally upstream of the mitochondrial apoptosis signaling cascade. More intriguingly, we find that it is sorafenib-induced ROS accumulation that enables TRAIL to activate caspase-8 in RCC. This leads to apoptosis that involves activation of an amplification loop via the mitochondrial apoptosis pathway. Thus, our mechanistic data indicate that sorafenib bypasses central resistance mechanisms through a direct induction of ΔΨ breakdown and ROS production. Activation of this pathway might represent a useful strategy to overcome the cell-inherent resistance to cancer therapeutics, including TRAIL, in multiresistant cancers such as RCC.
    Keywords: B Cell Lymphoma 2 (Bcl-2) Family ; Bak ; Bax ; Trail ; Apoptosis ; Cancer ; Drug Resistance ; Reactive Oxygen Species (Ros) ; Sorafenib ; Drug Resistance, Neoplasm ; Carcinoma, Renal Cell -- Metabolism ; Kidney Neoplasms -- Metabolism ; Mitochondria -- Metabolism ; Niacinamide -- Analogs & Derivatives ; Phenylurea Compounds -- Pharmacology ; Reactive Oxygen Species -- Metabolism
    E-ISSN: 1083-351X
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  • 8
    In: International Journal of Cancer, 01 January 2014, Vol.134(1), pp.235-243
    Description: Therapy‐induced senescence (TIS) as a permanent growth arrest can be induced by various stimuli, including anticancer compounds. TIS emerged as a promising strategy to overcome resistance phenomena. However, senescent cancer cells might regain proliferation activity or even secrete tumor‐promoting cytokines. Therefore, successful exploitation of TIS in cancer treatment simultaneously requires the development of effective strategies to eliminate senescent cancer cells. Virotherapy aims to selectively hit tumor cells, thus a combination with senescence‐inducing drugs was explored. As a model, we chose measles vaccine virus (MeV), which does not interfere with cellular senescence by itself. In different tumor cell types, such as hepatoma, pancreatic and mammary gland carcinoma, we demonstrate efficient viral replication and lysis after TIS by gemcitabine, doxorubicin or taxol. Applying real time imaging, we even found an accelerated lysis of senescent cancer cells, supporting an enhanced viral replication with an increase in cell‐associated and released infectious MeV particles. In summary, we show as a proof‐of‐concept that senescent tumor cells can be efficiently exploited as virus host cells by oncolytic MeV. These observations open up a new field for preclinical and clinical research to further investigate TIS and oncolytic viruses as an attractive combinatorial future treatment approach. What's new? Therapeutic induction of senescence (TIS) has emerged as a promising cancer treatment strategy with the potential to overcome therapy resistance due to the ability of tumor cells to evade apoptosis. Although senescent cells undergo a permanent cell cycle arrest, they remain metabolically active , making combination approaches to eliminate them urgently needed. This study provides a proof‐of‐concept that, despite the profoundly altered phenotype of senescent tumor cells, oncolytic viruses are able to hijack cancer cells after TIS, leading to a destruction of tumor cells. These observations open up a new research field at the crossroads between TIS and virotherapy.
    Keywords: Therapy‐Induced Senescence ; Virotherapy ; Hepatoma ; Pancreatic Cancer ; Breast Cancer
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 9
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  • 10
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, January 2014, Vol.28(1), pp.143-52
    Description: The transcription factors cAMP-responsive element binding protein (CREB) and cAMP-responsive element modulator (CREM) regulate gene transcription in response to elevated cAMP levels. The Crem isoform inducible cAMP early repressor (Icer) is transcribed by the internal promoter P2 as a critical regulator of multiple cellular processes. Here, we describe a novel inducible Crem isoform, small Icer (smIcer), regulated by a newly identified promoter (P6). ChIP revealed binding of CREB to P6 in human and mouse myocardium. P6 activity was induced by constitutively active CREB or stimulation of adenylyl cyclase. In mice, smIcer mRNA was ubiquitously expressed and transiently induced by β-adrenoceptor stimulation e.g., in heart and lung. SmICER repressed both basal and cAMP-induced activities of P6 and P2 promoters. Stimulation of adenylyl cyclase induced P2 and P6 in cell type-specific manner. Alternative translational start sites resulted in three different smICER proteins, linked to increased apoptosis sensitivity. In conclusion, the Crem gene provides two distinct and mutually controlled mechanisms of a cAMP-dependent induction of transcriptional repressors. Our results suggest not only that smICER is a novel regulator of cAMP-mediated gene regulation, but also emphasize that biological effects that have been ascribed solely to ICER, should be revised with regard to smICER.
    Keywords: Creb ; Apoptosis ; Camp ; Cyclic Amp ; Gene Regulation ; Transcription Factors ; Cyclic Amp Response Element Modulator -- Metabolism ; Promoter Regions, Genetic -- Genetics
    ISSN: 08926638
    E-ISSN: 1530-6860
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