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Berlin Brandenburg

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  • 1
    Language: English
    In: Journal of Investigative Dermatology, May 2008, Vol.128(5), pp.1134-1147
    Description: Death ligands not only activate a death program but also regulate inflammatory signalling pathways, for example, through NF-κB induction. Although tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF both activate NF-κB in human keratinocytes, only TRAIL potently induces apoptosis. However, when induction of NF-κB was inhibited with a kinase dead IKK2 mutant (IKK2-KD), TNF- but not TRAIL-induced apoptosis was dramatically enhanced. Acquired susceptibility to TNF-induced apoptosis was due to increased caspase-8 activation. To investigate the mechanism of resistance of HaCaT keratinocytes to TNF-induced apoptosis, we analyzed a panel of NF-κB-regulated effector molecules. Interestingly, the inhibitor of apoptosis protein (IAP) family member cIAP2, but not cIAP1, X-linked inhibitor of apoptosis, TNF receptor-associated factor (TRAF)-1, or TRAF2, was downregulated in sensitive but not in resistant HaCaT keratinocytes. Surprisingly, however, stable inducible expression of cIAP2 was not sufficient to render IKK2-KD-sensitized keratinocytes resistant to TNF, and reduction of cIAP2 alone did not increase the sensitivity of HaCaT keratinocytes to TNF. In conclusion, we demonstrate that inhibition of NF-κB dramatically sensitizes human keratinocytes to TNF- but not to TRAIL-induced apoptosis and that this sensitization for TNF was largely independent of cIAP2. Our data thus clearly exclude the candidates proposed to date to confer TNF apoptosis resistance and suggest the function of an unanticipated effector of NF-κB critical for the survival of HaCaT keratinocytes upstream or at the level of caspase-8 activation.
    Keywords: Medicine
    ISSN: 0022-202X
    E-ISSN: 1523-1747
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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: Nature communications, 25 September 2018, Vol.9(1), pp.3910
    Description: The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation and to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion of HOIP or HOIL-1 (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic and pharmacological evidence that the postnatal lethal dermatitis in Hoip and Hoil-1 mice is caused by TNFR1-induced, caspase-8-mediated apoptosis that occurs independently of the kinase activity of RIPK1. In the absence of TNFR1, however, dermatitis develops in adulthood, triggered by RIPK1-kinase-activity-dependent apoptosis and necroptosis. Strikingly, TRAIL or CD95L can redundantly induce this disease-causing cell death, as combined loss of their respective receptors is required to prevent TNFR1-independent dermatitis. These findings may have implications for the treatment of patients with mutations that perturb linear ubiquitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone.
    Keywords: Carrier Proteins -- Metabolism ; Dermatitis -- Metabolism ; Fas Ligand Protein -- Pharmacology ; Tnf-Related Apoptosis-Inducing Ligand -- Pharmacology ; Tumor Necrosis Factor-Alpha -- Pharmacology ; Ubiquitin-Protein Ligases -- Metabolism
    ISSN: Nature Communications
    E-ISSN: 2041-1723
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  • 4
    Language: English
    In: Nature, May 2018, Vol.557(7703), pp.112-117
    Description: The linear ubiquitin chain assembly complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR1 . Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, owing to deregulation of TNFR1-mediated cell death. In humans, deficiency in the third LUBAC component HOIL-1 causes autoimmunity and inflammatory disease, similar to HOIP deficiency, whereas HOIL-1 deficiency in mice was reported to cause no overt phenotype. Here we show, by creating HOIL-1-deficient mice, that HOIL-1 is as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is the catalytically active component of LUBAC, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1 signalling complex, thereby preventing aberrant cell death. Both HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity. Co-deletion of caspase-8 with RIPK3 or MLKL prevents cell death in Hoil-1 (also known as Rbck1) embryos, yet only the combined loss of caspase-8 with MLKL results in viable HOIL-1-deficient mice. Notably, triple-knockout Ripk3Casp8Hoil-1 embryos die at late gestation owing to haematopoietic defects that are rescued by co-deletion of RIPK1 but not MLKL. Collectively, these results demonstrate that both HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death. Furthermore, they reveal that when LUBAC and caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in fetal haematopoiesis.
    Keywords: Cell Death ; Embryonic Development ; Hematopoiesis ; Carrier Proteins -- Metabolism ; Ubiquitin -- Metabolism ; Ubiquitin-Protein Ligases -- Metabolism
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 5
    Language: English
    In: Langmuir : the ACS journal of surfaces and colloids, 05 October 2010, Vol.26(19), pp.15472-80
    Description: Despite tremendous progress in recent years, nanopatterning of hydrated polymeric systems such as hydrogels still represents a major challenge. Here, we employ block copolymer nanolithography to arrange gold nanoparticles on a solid template, followed by the transfer of the pattern to a polymeric hydrogel. In the next step, these nanoparticles serve as specific anchor points for active biomolecules. We demonstrate the engineering of poly(ethylene glycol) hydrogel surfaces with respect to elasticity, nanopatterning, and functionalization with biomolecules. For the first time, biomolecule arrangement on the nanometer scale and substrate stiffness can be varied independently from each other. Young's moduli, a measure of the compliance of the substrates, can be tuned over 4 orders of magnitude, including the values for all of the different tissues found in the human body. Structured hydrogels can be used to pattern any histidine-tagged protein as exemplified for his-protein A as an acceptor for immunoglobulin. When cell-adhesion-promoting peptide cRGDfK is selectively coupled to gold nanoparticles, the surfaces provide cues for cell-surface interaction and allow for the study of the modulation of cellular adhesion by the mechanical properties of the environment. Therefore, these substrates represent a unique multipurpose platform for studying receptor/ligand interactions with adhering cells, mechanotransduction, and cell-adhesion-dependent signaling.
    Keywords: Polymers -- Chemistry
    ISSN: 07437463
    E-ISSN: 1520-5827
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  • 6
    Language: English
    In: Journal of Experimental & Clinical Cancer Research, May 17, 2019, Vol.38(1)
    Description: Background Glioblastoma multiforme (GBM), due to its location, aggressiveness, heterogeneity and infiltrative growth, is characterized by an exceptionally dismal clinical outcome. The small molecule SI113, recently identified as a SGK1 inhibitor, has proven to be effective in restraining GBM growth in vitro and in vivo, showing also encouraging results when employed in combination with other antineoplastic drugs or radiotherapy. Our aim was to explore the pharmacological features of SI113 in GBM cells in order to elucidate the pivotal molecular pathways affected by the drug. Such knowledge would be of invaluable help in conceiving a rational offensive toward GBM. Methods We employed GBM cell lines, either established or primary (neurospheres), and used a Reverse-Phase Protein Arrays (RPPA) platform to assess the effect of SI113 upon 114 protein factors whose post-translational modifications are associated with activation or repression of specific signal transduction cascades. Results SI113 strongly affected the PI3K/mTOR pathway, evoking a pro-survival autophagic response in neurospheres. These results suggested the use of SI113 coupled, for maximum efficiency, with autophagy inhibitors. Indeed, the association of SI113 with an autophagy inhibitor, the antimalarial drug quinacrine, induced a strong synergistic effect in inhibiting GBM growth properties in all the cells tested, including neurospheres. Conclusions RPPA clearly identified the molecular pathways influenced by SI113 in GBM cells, highlighting their vulnerability when the drug was administered in association with autophagy inhibitors, providing a strong molecular rationale for testing SI113 in clinical trials in associative GBM therapy. Keywords: SI113, Glioblastoma multiforme, RPPA, Autophagy, Quinacrine
    Keywords: Cellular Signal Transduction -- Research ; Glioblastomas -- Research ; Glioblastomas -- Genetic Aspects ; Glioblastomas -- Drug Therapy ; Autophagy (Cytology) -- Research ; Quinacrine -- Usage ; Radiotherapy -- Usage
    ISSN: 0392-9078
    E-ISSN: 17569966
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  • 7
    Language: English
    In: Advances in experimental medicine and biology, 2011, Vol.691, pp.115-26
    Keywords: Signal Transduction ; Transcriptional Activation ; Apoptosis -- Genetics ; Multiprotein Complexes -- Metabolism ; Receptors, Tumor Necrosis Factor, Type I -- Metabolism ; Tumor Necrosis Factor-Alpha -- Metabolism ; Ubiquitin -- Metabolism
    ISBN: 9781441966117
    ISSN: 0065-2598
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 8
    Language: English
    In: Molecular & cellular proteomics : MCP, May 2018, Vol.17(5), pp.993-1009
    Description: Coimmunoprecipitation (co-IP) is one of the most frequently used techniques to study protein-protein (PPIs) or protein-nucleic acid interactions (PNIs). However, the presence of coprecipitated contaminants is a well-recognized issue associated with single-step co-IPs. To overcome this limitation, we developed the two-step co-IP (TIP) strategy that enables sequential coimmunoprecipitations of endogenous protein complexes. TIP can be performed with a broad range of mono- and polyclonal antibodies targeting a single protein or different components of a given complex. TIP results in a highly selective enrichment of protein complexes and thus outperforms single-step co-IPs for downstream applications such as mass spectrometry for the identification of PPIs and quantitative PCR for the analysis of PNIs. We benchmarked TIP for the identification of CD95/FAS-interacting proteins in primary human CD4 T cells, which recapitulated all major known interactors, but also enabled the proteomics discovery of PPM1G and IPO7 as new interaction partners. For its feasibility and high performance, we propose TIP as an advanced tool for the isolation of highly purified protein-protein and protein-nucleic acid complexes under native expression conditions.
    Keywords: Biology ; Anatomy & Physiology;
    ISSN: 15359476
    E-ISSN: 1535-9484
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  • 9
    In: Journal of Neuropathology & Experimental Neurology, 2014, Vol.73(11), pp.1034-1046
    Description: ABSTRACT: A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor–related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL-resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas.
    Keywords: Medicine;
    ISSN: 0022-3069
    E-ISSN: 15546578
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  • 10
    Language: English
    In: The Journal of Cell Biology, 06/15/2009, Vol.185(6), pp.i13-i13
    ISSN: 0021-9525
    E-ISSN: 1540-8140
    Source: CrossRef
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