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Berlin Brandenburg

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  • 1
    In: Thewes, Verena; Orso, Francesca; Jäger, Richard; Eckert, Dawid; Schäfer, Sabine; Kirfel, Gregor; Garbe, Stephan; Taverna, Daniela; Schorle, Hubert (2010). Interference with activator protein-2 transcription factors leads to induction of apoptosis and an increase in chemo- and radiation-sensitivity in breast cancer cells. BMC Cancer 10 ,
    Description: Background: Activator Protein-2 (AP-2) transcription factors are critically involved in a variety of fundamental cellular processes such as proliferation, differentiation and apoptosis and have also been implicated in carcinogenesis. Expression of the family members AP-2 alpha and AP-2 gamma is particularly well documented in malignancies of the female breast. Despite increasing evaluation of single AP-2 isoforms in mammary tumors the functional role of concerted expression of multiple AP-2 isoforms in breast cancer remains to be elucidated. AP-2 proteins can form homo-or heterodimers, and there is growing evidence that the net effect whether a cell will proliferate, undergo apoptosis or differentiate is partly dependent on the balance between different AP-2 isoforms. Methods: We simultaneously interfered with all AP-2 isoforms expressed in ErbB-2-positive murine N202.1A breast cancer cells by conditionally over-expressing a dominant-negative AP-2 mutant. Results: We show that interference with AP-2 protein function lead to reduced cell number, induced apoptosis and increased chemo-and radiation-sensitivity. Analysis of global gene expression changes upon interference with AP-2 proteins identified 139 modulated genes (90 up-regulated, 49 down-regulated) compared with control cells. Gene Ontology (GO) investigations for these genes revealed Cell Death and Cell Adhesion and Migration as the main functional categories including 25 and 12 genes, respectively. By using information obtained from Ingenuity Pathway Analysis Systems we were able to present proven or potential connections between AP-2 regulated genes involved in cell death and response to chemo-and radiation therapy, (i.e. Ctgf, Nrp1, Tnfaip3, Gsta3) and AP-2 and other main apoptosis players and to create a unique network. Conclusions: Expression of AP-2 transcription factors in breast cancer cells supports proliferation and contributes to chemo-and radiation-resistance of tumor cells by impairing the ability to induce apoptosis. Therefore, interference with AP-2 function could increase the sensitivity of tumor cells towards therapeutic intervention.
    Keywords: Tissue Growth-Factor ; Smooth-Muscle-Cells ; Differential Expression ; Mammary-Carcinoma ; Ap-2 Family ; Proliferation ; Overexpression ; Ap-2-Gamma ; Tumor ; Lung
    ISSN: 1471-2407
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  • 2
    In: PLoS ONE, 2013, Vol.8(8)
    Description: Maintenance and maturation of primordial germ cells is controlled by complex genetic and epigenetic cascades, and disturbances in this network lead to either infertility or malignant aberration. Transcription factor TFAP2C has been described to be essential for primordial germ cell maintenance and to be upregulated in several human germ cell cancers. Using global gene expression profiling, we identified genes deregulated upon loss of Tfap2c in embryonic stem cells and primordial germ cell-like cells. We show that loss of Tfap2c affects many aspects of the genetic network regulating germ cell biology, such as downregulation of maturation markers and induction of markers indicative for somatic differentiation, cell cycle, epigenetic remodeling and pluripotency. Chromatin-immunoprecipitation analyses demonstrated binding of TFAP2C to regulatory regions of deregulated genes ( Sfrp1, Dmrt1 , Nanos3 , c-Kit , Cdk6 , Cdkn1a , Fgf4 , Klf4 , Dnmt3b and Dnmt3l ) suggesting that these genes are direct transcriptional targets of TFAP2C in primordial germ cells. Since Tfap2c deficient primordial germ cell-like cells display cancer related deregulations in epigenetic remodeling, cell cycle and pluripotency control, the Tfap2c -knockout allele was bred onto 129S2/Sv genetic background. There, mice heterozygous for Tfap2c develop with high incidence germ cell cancer resembling human pediatric germ cell tumors. Precursor lesions can be observed as early as E16.5 in developing testes displaying persisting expression of pluripotency markers. We further demonstrate that mice with a heterozygous deletion of the TFAP2C target gene Nanos3 are also prone to develop teratomas. These data highlight TFAP2C as a critical and dose-sensitive regulator of germ cell fate.
    Keywords: Research Article ; Biology ; Medicine
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Developmental Dynamics, March 2010, Vol.239(3), pp.1027-1033
    Description: Extensive development of the mammary gland occurs during puberty, when rising levels of ovarian hormones induce the formation of highly proliferative terminal end buds (TEBs) at the tips of mammary ducts. TEBs consist of an outer layer of cap cells and of inner body cells. TEBs invade the adipose stroma and bifurcate while extending the ducts to generate an arborized ductal network. We show that in murine mammary glands transcription factor AP‐2γ is strongly expressed in the cap cell layer and in a subset of body cells of TEBs. To decipher AP‐2γ functions during mammary development we generated AP‐2γ‐deficient mice. Their mammary glands displayed impaired ductal branching and elongation. Cellular proliferation within TEBs was reduced. Although estrogen receptor was expressed, exogenously administered ovarian hormones could not restore normal development. Therefore, AP‐2γ is functionally involved in branching morphogenesis of the mammary epithelium, possibly by controlling genetic processes downstream of ovarian hormones. Developmental Dynamics 239:1027–1033, 2010. © 2010 Wiley‐Liss, Inc.
    Keywords: Ap‐2 ; Tfap2c ; Mammary ; Branching Morphogenesis ; Transgenic Mice
    ISSN: 1058-8388
    E-ISSN: 1097-0177
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  • 4
    Language: English
    In: Genome biology, 19 June 2014, Vol.15(6), pp.R79
    Description: RNA editing encompasses a post-transcriptional process in which the genomically templated sequence is enzymatically altered and introduces a modified base into the edited transcript. Mammalian C-to-U RNA editing represents a distinct subtype of base modification, whose prototype is intestinal apolipoprotein B mRNA, mediated by the catalytic deaminase Apobec-1. However, the genome-wide identification, tissue-specificity and functional implications of Apobec-1-mediated C-to-U RNA editing remain incompletely explored. Deep sequencing, data filtering and Sanger-sequence validation of intestinal and hepatic RNA from wild-type and Apobec-1-deficient mice revealed 56 novel editing sites in 54 intestinal mRNAs and 22 novel sites in 17 liver mRNAs, all within 3' untranslated regions. Eleven of 17 liver RNAs shared editing sites with intestinal RNAs, while 6 sites are unique to liver. Changes in RNA editing lead to corresponding changes in intestinal mRNA and protein levels for 11 genes. Analysis of RNA editing in vivo following tissue-specific Apobec-1 adenoviral or transgenic Apobec-1 overexpression reveals that a subset of targets identified in wild-type mice are restored in Apobec-1-deficient mouse intestine and liver following Apobec-1 rescue. We find distinctive polysome profiles for several RNA editing targets and demonstrate novel exonic editing sites in nuclear preparations from intestine but not hepatic apolipoprotein B RNA. RNA editing is validated using cell-free extracts from wild-type but not Apobec-1-deficient mice, demonstrating that Apobec-1 is required. These studies define selective, tissue-specific targets of Apobec-1-dependent RNA editing and show the functional consequences of editing are both transcript- and tissue-specific.
    Keywords: RNA Editing ; Cytidine Deaminase -- Genetics ; Intestine, Small -- Enzymology ; Liver -- Enzymology
    E-ISSN: 1474-760X
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  • 5
    Language: English
    In: Biology of Reproduction, 2010, Vol.82(1), pp.214-223
    Description: textabstractFormation of the germ cell lineage involves multiple processes, including repression of somatic differentiation and reacquisition of pluripotency as well as a unique epigenetic constitution. The transcriptional regulator Prdm1 has been identified as a main coordinator of this process, controlling...
    Keywords: Ap-2γ ; B Lymphocyte Induced Maturation Protein 1 ; Dna Glycosylase Muty ; Dazl Protein ; Developmental Biology ; Gamete Biology ; Gene Regulation ; Hoxb1 ; Myod1 Protein ; Nanos 3 Protein ; Prdm1 ; Prdm1 Protein ; Primordial Germ Cells ; Somatic Differentiation ; Tcfap2c ; Tcam-2 ; Tcfap2c Protein ; Aminomethyltransferase ; Animal ; Animal Experiment ; Animal Tissue ; Apoptosis ; Article ; Binding Protein ; Biological Marker ; Cell Differentiation ; Controlled Study ; Development And Aging ; Dipeptide Binding Protein ; Embryo ; Embryo Cell ; Embryo Development ; Female ; Gene Expression Regulation ; Germ Cell ; Growth ; Homeobox B1 Protein ; In Vitro Study ; Male ; Membrane Protein ; Mesoderm ; Metabolism ; Mouse ; Mutant ; Nonhuman ; Primordial Germ Cell ; Priority Journal ; Protein Function ; Reproduction ; Transcription Factor ; Transcription Factor Ap 2 ; Transcription Factor Hand 1 ; Transcription Factor Hoxa 1 ; Transcription Factor Tcfap2c ; Transgenic Mouse ; Unclassified Drug ; Upregulation
    ISSN: 00063363
    E-ISSN: 15297268
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  • 6
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 05 July 2011, Vol.108(27), pp.11187-92
    Description: We describe a generic approach to assemble correctly two heavy and two light chains, derived from two existing antibodies, to form human bivalent bispecific IgG antibodies without use of artificial linkers. Based on the knobs-into-holes technology that enables heterodimerization of the heavy chains, correct association of the light chains and their cognate heavy chains is achieved by exchange of heavy-chain and light-chain domains within the antigen binding fragment (Fab) of one half of the bispecific antibody. This "crossover" retains the antigen-binding affinity but makes the two arms so different that light-chain mispairing can no longer occur. Applying the three possible "CrossMab" formats, we generated bispecific antibodies against angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A) and show that they can be produced by standard techniques, exhibit stabilities comparable to natural antibodies, and bind both targets simultaneously with unaltered affinity. Because of its superior side-product profile, the CrossMab(CH1-CL) was selected for in vivo profiling and showed potent antiangiogenic and antitumoral activity.
    Keywords: Antibodies, Bispecific -- Biosynthesis ; Immunoglobulin G -- Biosynthesis
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 7
    Language: English
    In: Analytical and Bioanalytical Chemistry, 2013, Vol.405(22), pp.6959-6968
    Description: An atmospheric pressure laser desorption/ionization mass spectrometry imaging ion source has been developed that combines high spatial resolution and high mass resolution for the in situ analysis of biological tissue. The system is based on an infrared laser system working at 2.94 to 3.10 μm wavelength, employing a Nd:YAG laser-pumped optical parametrical oscillator. A Raman-shifted Nd:YAG laser system was also tested as an alternative irradiation source. A dedicated optical setup was used to focus the laser beam, coaxially with the ion optical axis and normal to the sample surface, to a spot size of 30 μm in diameter. No additional matrix was needed for laser desorption/ionization. A cooling stage was developed to reduce evaporation of physiological cell water. Ions were formed under atmospheric pressure and transferred by an extended heated capillary into the atmospheric pressure inlet of an orbital trapping mass spectrometer. Various phospholipid compounds were detected, identified, and imaged at a pixel resolution of up to 25 μm from mouse brain tissue sections. Mass accuracies of better than 2 ppm and a mass resolution of 30,000 at m / z  = 400 were achieved for these measurements. Figure Infrared laser desorption/ionization mass spectrometry imaging provides for direct analysis of biological tissue with a high spatial resolution of 25 μm
    Keywords: Mass spectrometry imaging ; Infrared laser desorption/ionization ; Accurate mass ; High-resolution MS ; High spatial resolution ; Atmospheric pressure ; In situ analysis
    ISSN: 1618-2642
    E-ISSN: 1618-2650
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  • 8
    Language: English
    In: The Journal of clinical investigation, November 2012, Vol.122(11), pp.3965-76
    Description: Psoriasis is a chronic inflammatory disorder of the skin affecting approximately 2% of the world's population. Accumulating evidence has revealed that the IL-23/IL-17/IL-22 pathway is key for development of skin immunopathology. However, the role of keratinocytes and their crosstalk with immune cells at the onset of disease remains poorly understood. Here, we show that IL-36R-deficient (Il36r-/-) mice were protected from imiquimod-induced expansion of dermal IL-17-producing γδ T cells and psoriasiform dermatitis. Furthermore, IL-36R antagonist-deficient (Il36rn-/-) mice showed exacerbated pathology. TLR7 ligation on DCs induced IL-36-mediated crosstalk with keratinocytes and dermal mesenchymal cells that was crucial for control of the pathological IL-23/IL-17/IL-22 axis and disease development. Notably, mice lacking IL-23, IL-17, or IL-22 were less well protected from disease compared with Il36r-/- mice, indicating an additional distinct activity of IL-36 beyond induction of the pathological IL-23 axis. Moreover, while the absence of IL-1R1 prevented neutrophil infiltration, it did not protect from acanthosis and hyperkeratosis, demonstrating that neutrophils are dispensable for disease manifestation. These results highlight a central and unique IL-1-independent role for IL-36 in control of the IL-23/IL-17/IL-22 pathway and development of psoriasiform dermatitis.
    Keywords: Cell Communication -- Immunology ; Dendritic Cells -- Immunology ; Dermatitis -- Immunology ; Interleukin-1 -- Immunology ; Keratinocytes -- Immunology ; Psoriasis -- Immunology
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 9
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(2), p.e56625
    Description: The nuclear factor erythroid 2-related factor 2 (Nrf2) governs the expression of antioxidant and phase II detoxifying enzymes. Nrf2 activation can prevent or reduce cellular damage associated with several types of injury in many different tissues and organs. Dominant mutations in Cu/Zn-superoxide...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: Seminars in Immunology, August 2014, Vol.26(4), pp.321-328
    Description: The attraction and activation of immune cells is an important response of the skin to injury and allows an efficient defense against invading pathogens. In addition, immune cells fulfill various functions that are important for the repair process. An exaggerated inflammatory response, however, is a hallmark of chronic, non-healing wounds. Therefore, it is essential to strictly control and coordinate the levels and activities of various immune cells in normal and wounded skin. Recent studies provided insight into the molecular mechanisms underlying the inflammatory response after wounding, and various transcriptional regulators involved in this process have been identified. This review summarizes our current knowledge on the function of different transcription factors in wound repair, with particular emphasis on proteins with a documented role in the control of wound inflammation.
    Keywords: Granulation Tissue ; Inflammation ; Transcription Factor ; Scar ; Medicine ; Biology
    ISSN: 1044-5323
    E-ISSN: 1096-3618
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