Kooperativer Bibliotheksverbund

Berlin Brandenburg


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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 09 July 2013, Vol.110(28), pp.E2592-601
    Description: Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.
    Keywords: Hdac Inhibitor ; Childhood Tumors ; Drug Resistance ; Autophagy -- Physiology ; Cell Survival -- Physiology ; Histone Deacetylases -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Experimental Dermatology, October 2015, Vol.24(10), pp.785-787
    Description: The mucin‐like transmembrane protein podoplanin () is prominently represented in tumor‐associated gene expression signatures of numerous types of cancer including squamous cell carcinoma, and gain‐of‐function and knockdown approaches in tissue culture strongly suggested an important role of in cell proliferation, migration and adhesion. is absent during epidermal homeostasis but is highly expressed in basal keratinocytes during cutaneous wound healing. Enhanced motility of immortalized keratinocytes upon ectopic overexpression argues for wound healing defects upon podoplanin deficiency in keratinocytes; however, data that unequivocally define the impact of by functional studies in a physiologically relevant system are still missing. Here, we have applied an loss‐of‐function approach by generating a novel transgenic mouse line with keratinocyte‐specific podoplanin deficiency. Performing cutaneous full‐thickness excisional wounds to examine re‐epithelialization capacity, unexpectedly, no defects were observed in wound healing properties of mutant mice. Similarly, ‐deficient primary keratinocytes showed no impairment in migration, adhesion or proliferation. Thus, function is not rate‐limiting for re‐epithelialization but may be functionally compensated by an as yet unknown protein. Our data also call for functional studies on in settings of skin tumor development and progression to clarify 's role in skin pathology.
    Keywords: Conditional Knockout ; Keratinocytes ; Podoplanin ; Skin ; Wound Healing
    ISSN: 0906-6705
    E-ISSN: 1600-0625
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  • 3
    Language: English
    In: The Journal of clinical investigation, July 2010, Vol.120(7), pp.2307-18
    Description: Cellular contractility and, thus, the ability to alter cell shape are prerequisites for a number of important biological processes such as cytokinesis, movement, differentiation, and substrate adherence. The contractile capacity of vascular smooth muscle cells (VSMCs) is pivotal for the regulation of vascular tone and thus blood pressure and flow. Here, we report that conditional ablation of the transcriptional regulator Junb results in impaired arterial contractility in vivo and in vitro. This was exemplified by resistance of Junb-deficient mice to DOCA-salt-induced volume-dependent hypertension as well as by a decreased contractile capacity of isolated arteries. Detailed analyses of Junb-deficient VSMCs, mouse embryonic fibroblasts, and endothelial cells revealed a general failure in stress fiber formation and impaired cellular motility. Concomitantly, we identified myosin regulatory light chain 9 (Myl9), which is critically involved in actomyosin contractility and stress fiber assembly, as a Junb target. Consistent with these findings, reexpression of either Junb or Myl9 in Junb-deficient cells restored stress fiber formation, cellular motility, and contractile capacity. Our data establish a molecular link between the activator protein-1 transcription factor subunit Junb and actomyosin-based cellular motility as well as cellular and vascular contractility by governing Myl9 transcription.
    Keywords: Gene Expression Regulation ; Cell Movement -- Physiology ; Muscle, Smooth, Vascular -- Metabolism ; Myocytes, Smooth Muscle -- Metabolism ; Proto-Oncogene Proteins C-Jun -- Metabolism
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 4
    Language: English
    In: International Journal of Radiation Oncology, Biology, Physics, 2010, Vol.77(2), pp.582-590
    Description: Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMP13 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse. We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57Bl/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome. We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5–6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival. Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis.
    Keywords: Mmp13 ; Ionizing Radiation ; Pulmonary Fibrosis ; Volume Computed Tomography ; Medicine
    ISSN: 0360-3016
    E-ISSN: 1879-355X
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  • 5
    Language: English
    In: Arthritis research & therapy, 2013, Vol.15(6), pp.R222
    Description: Matrix metalloproteinases (MMPs) are important in tissue remodelling. Here we investigate the role of collagenase-3 (MMP-13) in antibody-induced arthritis. For this study we employed the K/BxN serum-induced arthritis model. Arthritis was induced in C57BL/6 wild type (WT) and MMP-13-deficient (MMP-13–/–) mice by intraperitoneal injection of 200 μl of K/BxN serum. Arthritis was assessed by measuring the ankle swelling. During the course of the experiments, mice were sacrificed every second day for histological examination of the ankle joints. Ankle sections were evaluated histologically for infiltration of inflammatory cells, pannus tissue formation and bone/cartilage destruction. Semi-quantitative PCR was used to determine MMP-13 expression levels in ankle joints of untreated and K/BxN serum-injected mice. This study shows that MMP-13 is a regulator of inflammation. We observed increased expression of MMP-13 in ankle joints of WT mice during K/BxN serum-induced arthritis and both K/BxN serum-treated WT and MMP-13–/– mice developed progressive arthritis with a similar onset. However, MMP-13–/– mice showed significantly reduced disease over the whole arthritic period. Ankle joints of WT mice showed severe joint destruction with extensive inflammation and erosion of cartilage and bone. In contrast, MMP-13–/– mice displayed significantly decreased severity of arthritis (50% to 60%) as analyzed by clinical and histological scoring methods. MMP-13 deficiency acts to suppress the local inflammatory responses. Therefore, MMP-13 has a role in the pathogenesis of arthritis, suggesting MMP-13 is a potential therapeutic target.
    Keywords: Arthritis, Experimental -- Enzymology ; Arthritis, Rheumatoid -- Enzymology ; Matrix Metalloproteinase 13 -- Metabolism
    ISSN: 14786354
    E-ISSN: 1478-6362
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  • 6
    In: Journal of Investigative Dermatology, 2010, Vol.130(7), p.1922
    Description: Recently, we identified an AP-1-dependent target gene in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated mouse back skin, which encodes a retroviral-like aspartic proteinase (Taps/Asprv1). Taps expression was detected almost exclusively in stratified epithelia of mouse embryos and adult tissues, and enhanced protein levels were present in several non-neoplastic human skin disorders, implicating a crucial role for differentiation and homeostasis of multilayered epithelia. Here, we generated a mouse model in which Taps transgene expression is under the control of the human ubiquitin C promoter (UBC-Taps). Although no obvious phenotype was observed in normal skin development and homeostasis, these mice showed a significant delay in cutaneous wound closure compared with control animals. Shortly after re-epithelialization, we found an increase in keratinocytes in the stratum granulosum, which express Filaggrin, a late differentiation marker. A hypergranulosum-like phenotype with increased numbers of Filaggrin-positive keratinocytes was also observed in UBC-Taps mice after administration of TPA. In summary, these data show that aberrant Taps expression causes impaired skin regeneration and skin remodeling after cutaneous injury and chemically induced hyperplasia.
    Keywords: Medicine;
    ISSN: 0022-202X
    E-ISSN: 15231747
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  • 7
    Language: English
    In: The Journal of biological chemistry, 27 September 2002, Vol.277(39), pp.35961-8
    Description: JunB, a major component of the AP-1 transcription factor, is known to act antagonistically to c-Jun in transcriptional regulation and is proposed to be a negative regulator of cell proliferation. Employing fibroblasts derived from E9.5 junB(-/-) mouse embryos we provide evidence for a novel cell cycle promoting role of JunB. Despite a normal proliferation rate, primary and immortalized junB(-/-) fibroblasts exhibited an altered cell cycle profile, which was characterized by an increase in the population of S-phase cells, while that of cells in G(2)/M-phase was diminished. This delay in G(2)/M-transition is caused by impaired cyclin A-CDK2 and cyclin B-CDC2 kinase activities and counteracts the accelerated S-phase entry. Cells lacking JunB show severely delayed kinetics of cyclin A mRNA expression due to the loss of proper transcriptional activation mediated via binding of JunB to the CRE element in the cyclin A promoter. Upon reintroduction of an inducible JunB-ER(TM) expression vector the cell cycle distribution and the cell cycle-associated cyclin A-CDK2 kinase activity could be restored. Thus, cyclin A is a direct transcriptional target of JunB driving cell proliferation.
    Keywords: Cyclin A -- Metabolism ; Proto-Oncogene Proteins C-Jun -- Physiology
    ISSN: 0021-9258
    E-ISSN: 1083351X
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  • 8
    Language: English
    In: The Journal of cell biology, 18 December 2006, Vol.175(6), pp.981-91
    Description: The molecular mechanism triggering the organization of endothelial cells (ECs) in multicellular tubules is mechanistically still poorly understood. We demonstrate that cell-autonomous endothelial functions of the AP-1 subunit JunB are required for proper endothelial morphogenesis both in vivo in mouse embryos with endothelial-specific ablation of JunB and in in vitro angiogenesis models. By cDNA microarray analysis, we identified core-binding factor beta (CBFbeta), which together with the Runx proteins forms the heterodimeric core-binding transcription complex CBF, as a novel JunB target gene. In line with our findings, expression of the CBF target MMP-13 was impaired in JunB-deficient ECs. Reintroduction of CBFbeta into JunB-deficient ECs rescued the tube formation defect and MMP-13 expression, indicating an important role for CBFbeta in EC morphogenesis.
    Keywords: Morphogenesis ; Core Binding Factor Beta Subunit -- Metabolism ; Endothelium, Vascular -- Cytology ; Proto-Oncogene Proteins C-Jun -- Physiology
    ISSN: 0021-9525
    E-ISSN: 15408140
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  • 9
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 01 January 2006, Vol.176(1), pp.7-11
    Description: The activating receptor NKG2D and its ligands RAE-1 play an important role in the NK, gammadelta+, and CD8+ T cell-mediated immune response to tumors. Expression levels of RAE-1 on target cells have to be tightly controlled to allow immune cell activation against tumors but to avoid destruction of healthy tissues. In this study, we report that cell surface expression of RAE-1epsilon is greatly enhanced on cells lacking JunB, a subunit of the transcription complex AP-1. Furthermore, tissue-specific junB knockout mice respond to 12-O-tetradecanoyl-phorbol-13-acetate, a potent AP-1 activator, with markedly increased and sustained epidermal RAE-1epsilon expression. Accordingly, junB-deficient cells are efficiently killed via NKG2D by NK cells and induce IFN-gamma production. Our data indicate that the transcription factor AP-1, which is involved in tumorigenesis and cellular stress responses, regulates RAE-1epsilon. Thus, up-regulated RAE-1epsilon expression due to low levels of JunB could alert immune cells to tumors and stressed cells.
    Keywords: Cytotoxicity, Immunologic -- Immunology ; Killer Cells, Natural -- Immunology ; Lymphocyte Subsets -- Immunology ; Membrane Proteins -- Biosynthesis ; Receptors, Immunologic -- Immunology ; Transcription Factor AP-1 -- Immunology
    ISSN: 0022-1767
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 10
    Language: English
    In: Scientific reports, 13 October 2015, Vol.5, pp.15007
    Description: JUNB, a subunit of the AP-1 transcription factor complex, mediates gene regulation in response to a plethora of extracellular stimuli. Previously, JUNB was shown to act as a critical positive regulator of blood vessel development and homeostasis as well as a negative regulator of proliferation, inflammation and tumour growth. Here, we demonstrate that the oncogenic miR-182 is a novel JUNB target. Loss-of-function studies by morpholino-mediated knockdown and the CRISPR/Cas9 technology identify a novel function for both JUNB and its target miR-182 in lymphatic vascular development in zebrafish. Furthermore, we show that miR-182 attenuates foxo1 expression indicating that strictly balanced Foxo1 levels are required for proper lymphatic vascular development in zebrafish. In conclusion, our findings uncover with the Junb/miR-182/Foxo1 regulatory axis a novel key player in governing lymphatic vascular morphogenesis in zebrafish.
    Keywords: Gene Expression Regulation ; Lymphangiogenesis ; Micrornas -- Genetics ; Proto-Oncogene Proteins C-Jun -- Metabolism ; Zebrafish -- Genetics
    E-ISSN: 2045-2322
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