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Berlin Brandenburg

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  • 1
    Lexicon Article
    Lexicon Article
    Language: English
    In: Encyclopedia of Cancer
    ISBN: 978-3-642-16483-5
    Source: Gale Virtual Reference Library (GVRL)
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  • 2
    Language: English
    In: Cancer Research, 08/01/2015, Vol.75(15 Supplement), pp.2708-2708
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 3
    Language: English
    In: Cancer Research, 08/01/2015, Vol.75(15 Supplement), pp.969-969
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    Language: English
    In: BBA - Molecular Cell Research, November 2015, Vol.1853(11), pp.2847-2855
    Description: Scaffold proteins are multidomain proteins without enzymatic function that play a central role in coordinating signaling processes. The scaffold protein CNK1 interacts with pathway-specific signaling proteins and thereby regulates these respective pathways. Here, we revealed tyrosine phosphorylation as a critical regulation mechanism to control the function of CNK1. We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. Contrary, mutants preventing tyrosine phosphorylation promote matrix metalloproteinase MMP14 promoter activity. CNK1-driven cell proliferation partially depends on its tyrosine phosphorylation. Upon PDGF stimulation, CNK1 is recruited to the plasma membrane mediated by SRC. Knock down of CNK1 prevents PDGF-induced SRE-dependent gene expression, MMP14 promoter activity and cell proliferation. Thus, tyrosine phosphorylation is an important mechanism to control the subcellular localization of CNK1 and its distinct biological functions.
    Keywords: Cnk1 ; Platelet-Derived Growth Factor ; Scaffold Protein ; Signal Transduction ; Src ; Tyrosine Phosphorylation ; Biology ; Chemistry
    ISSN: 0167-4889
    E-ISSN: 1879-2596
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  • 5
    In: Chemical Communications, 2013, Vol.49(53), pp.5927-5929
    Description: The caging of small molecules has revolutionized biological research by providing a means to regulate a wide range of processes. Here we report on a generic pharmacological method to cage proteins in a similar fashion. The present approach is of value in both fundamental and applied research, e.g. in tissue engineering.
    Keywords: Tissue Engineering ; Intercellular Signaling Peptides and Proteins -- Administration & Dosage;
    ISSN: 1359-7345
    E-ISSN: 1364-548X
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  • 6
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.2854-2854
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 7
    Language: English
    In: Oncogene, 2018, Vol.37(12), pp.1576-1593
    Description: BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAF oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab. First results of these combinatorial studies demonstrated improved efficacy, however, the response rates still were heterogeneous. Here, we show that BRAF inhibition leads to the upregulation of a variety of receptor tyrosine kinases (RTKs) in CRC cell lines, including not only the EGFR, but also human epidermal growth factor receptor (HER) 2 and HER3. Importantly, combination of the BRAF inhibitors (BRAFi) vemurafenib (PLX4032), dabrafenib, or encorafenib with inhibitors dually targeting the EGFR and HER2 (such as lapatinib, canertinib, and afatinib) significantly reduced the metabolic activity and proliferative potential of CRC cells. This re-sensitization was also observed after genetic depletion of HER2 or HER3. Interestingly, BRAF inhibitors did not only upregulate RTKs, but also increased the abundance of the GRB2-associated binders (Gab) 1 and Gab2, two important amplifiers of RTK signaling. An allele-specific shRNA-mediated knockdown of BRAF revealed that Gab2 upregulation was directly dependent on the loss of the oncoprotein and was not caused by an “off-target” effect of these kinase inhibitors. Furthermore, Gab2 and Gab2-mediated Shp2 signaling were shown to be functionally important in BRAFi resistance. These findings highlight potential new escape mechanisms to these targeted therapies and indicate that a broad suppression of RTK signaling might be beneficial and should be taken into account in future research addressing targeted therapy in BRAF-mutant CRC.
    Keywords: Gene Mutation – Research ; Transcription (Genetics) – Research ; Tyrosine – Research ; Cancer Cells – Research ; Colorectal Cancer – Genetic Aspects ; Colorectal Cancer – Research;
    ISSN: 0950-9232
    E-ISSN: 14765594
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  • 8
    Language: English
    In: Cell Communication and Signaling, July 13, 2011, Vol.9, p.17
    Description: Introduction Non-transformed mammary epithelial cell lines such as MCF-10A recapitulate epithelial morphogenesis in three-dimensional (3D) tissue culture by forming acinar structures. They represent an important tool to characterize the biological properties of oncogenes and to model early carcinogenic events. So far, however, these approaches were restricted to cells with constitutive oncogene expression prior to the set-up of 3D cultures. Although very informative, this experimental setting has precluded the analysis of effects caused by sudden oncoprotein expression or withdrawal in established epithelial cultures. Here, we report the establishment and use of a stable MCF-10A cell line (MCF-10Atet) fitted with a novel and improved doxycycline (dox)-regulated expression system allowing the conditional expression of any transgene. Methods MCF-10Atet cells were generated by stable transfection with pWHE644, a vector expressing a second generation tetracycline-regulated transactivator and a novel transcriptional silencer. In order to test the properties of this new repressor/activator switch, MCF-10Atet cells were transfected with a second plasmid, pTET-HABRAF-IRES-GFP, which responds to dox treatment with the production of a bi-cistronic transcript encoding hemagglutinin-tagged B-Raf and green fluorescent protein (GFP). This improved conditional expression system was then characterized in detail in terms of its response to various dox concentrations and exposure times. The plasticity of the phenotype provoked by oncogenic B-Raf.sup.V600E .sup.in MCF-10Atet cells was analyzed in 3D cultures by dox exposure and subsequent wash-out. Results MCF-10Atet cells represent a tightly controlled, conditional gene expression system. Using B-Raf.sup.V600E .sup.as a model oncoprotein, we show that its sudden expression in established 3D cultures results in the loss of acinar organization, the induction of an invasive phenotype and hallmarks of epithelial-to-mesenchymal transition (EMT). Importantly, we show for the first time that this severe transformed phenotype can be reversed by dox wash-out and concomitant termination of oncogene expression. Conclusions Taken together, we have generated a stable MCF-10A subline allowing tight dox-controlled and reversible expression of any transgene without the need to modify its product by introducing artificial dimerization or ligand-binding domains. This system will be very valuable to address phenomena such as EMT, oncogene addiction, oncogene-induced senescence and drug resistance.
    Keywords: Epithelial Cells -- Physiological Aspects ; Epithelial Cells -- Genetic Aspects ; Epithelial Cells -- Research ; Gene Expression -- Research ; Oncogenes -- Physiological Aspects ; Oncogenes -- Research
    ISSN: 1478-811X
    Source: Cengage Learning, Inc.
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  • 9
    Language: English
    In: Cell Communication and Signaling, July 13, 2011, Vol.9, p.17
    Description: Introduction Non-transformed mammary epithelial cell lines such as MCF-10A recapitulate epithelial morphogenesis in three-dimensional (3D) tissue culture by forming acinar structures. They represent an important tool to characterize the biological properties of oncogenes and to model early carcinogenic events. So far, however, these approaches were restricted to cells with constitutive oncogene expression prior to the set-up of 3D cultures. Although very informative, this experimental setting has precluded the analysis of effects caused by sudden oncoprotein expression or withdrawal in established epithelial cultures. Here, we report the establishment and use of a stable MCF-10A cell line (MCF-10Atet) fitted with a novel and improved doxycycline (dox)-regulated expression system allowing the conditional expression of any transgene. Methods MCF-10Atet cells were generated by stable transfection with pWHE644, a vector expressing a second generation tetracycline-regulated transactivator and a novel transcriptional silencer. In order to test the properties of this new repressor/activator switch, MCF-10Atet cells were transfected with a second plasmid, pTET-HABRAF-IRES-GFP, which responds to dox treatment with the production of a bi-cistronic transcript encoding hemagglutinin-tagged B-Raf and green fluorescent protein (GFP). This improved conditional expression system was then characterized in detail in terms of its response to various dox concentrations and exposure times. The plasticity of the phenotype provoked by oncogenic B-Raf.sup.V600E .sup.in MCF-10Atet cells was analyzed in 3D cultures by dox exposure and subsequent wash-out. Results MCF-10Atet cells represent a tightly controlled, conditional gene expression system. Using B-Raf.sup.V600E .sup.as a model oncoprotein, we show that its sudden expression in established 3D cultures results in the loss of acinar organization, the induction of an invasive phenotype and hallmarks of epithelial-to-mesenchymal transition (EMT). Importantly, we show for the first time that this severe transformed phenotype can be reversed by dox wash-out and concomitant termination of oncogene expression. Conclusions Taken together, we have generated a stable MCF-10A subline allowing tight dox-controlled and reversible expression of any transgene without the need to modify its product by introducing artificial dimerization or ligand-binding domains. This system will be very valuable to address phenomena such as EMT, oncogene addiction, oncogene-induced senescence and drug resistance.
    Keywords: Drug Resistance -- Genetic Aspects ; Gene Expression ; Fluorescence
    ISSN: 1478-811X
    Source: Cengage Learning, Inc.
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  • 10
    Language: English
    In: Cancer Research, 07/01/2017, Vol.77(13 Supplement), pp.5170-5170
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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