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  • 1
    Language: English
    In: Life Sciences, 2011, Vol.89(9), pp.304-312
    Description: Members of the epidermal growth factor receptor (EGFR) family represent validated targets for anti-cancer therapy and EGFR inhibitors have also shown efficacy in pancreatic carcinoma. We here described in detail molecular forms of the EGF receptor released by pancreatic cancer cells. We found peptides specific for the EGFR in the secretomes of five pancreatic cancer cell lines. Secretomes from cultured cancer cells are widely used as sources for serum biomarker discovery. The detailed analysis of EGFR forms in secretomes of human pancreatic cancer cells is a compilation of results from mass spectrometry (MS) and Western blotting with intracellular and extracellular domain specific antibodies. Pancreatic cancer cells secrete a 110 kDa soluble form of the EGFR (sEGFR) representing the ligand binding extracellular EGFR domains and presumably released by ectodomain shedding. At the same time, as constituents of exosomes, the EGFR is released as full-length intact receptor (170 kDa) and as a 65 kDa processed form, the C-terminal remnant fragment that corresponds to the intracellular kinase domain. The detailed characterization of diverse EGFR forms released by pancreatic cancer cells in vitro and presumably in vivo bears important implications for functional studies, for the validation of soluble EGFR as a serum biomarker and for the design of targeted therapies.
    Keywords: Egfr Forms ; Secretome ; Exosome ; Proteomics ; Targeted Therapy ; Biomarker ; Pancreatic Cancer ; Sciences (General) ; Biology
    ISSN: 0024-3205
    E-ISSN: 1879-0631
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  • 2
    Language: English
    In: Molecular Cell, 27 July 2012, Vol.47(2), pp.306-319
    Description: The CD95 (Fas/APO-1) death-inducing signaling complex (DISC) is essential for the initiation of CD95-mediated apoptotic and nonapoptotic responses. The CD95 DISC comprises CD95, FADD, procaspase-8, procaspase-10, and c-FLIP proteins. Procaspase-8 and procaspase-10 are activated at the DISC, leading to the formation of active caspases and apoptosis initiation. In this study we analyzed the stoichiometry of the CD95 DISC. Using quantitative western blots, mass spectrometry, and mathematical modeling, we reveal that the amount of DED proteins procaspase-8/procaspase-10 and c-FLIP at the DISC exceeds that of FADD by several-fold. Furthermore, our findings imply that procaspase-8, procaspase-10, and c-FLIP could form DED chains at the DISC, enabling the formation of dimers and efficient activation of caspase-8. Taken together, our findings provide an enhanced understanding of caspase-8 activation and initiation of apoptosis at the DISC. ► The amount of procaspase-8/procaspase-10 and c-FLIP at the DISC exceeds that of FADD ► Procaspase-8, procaspase-10, and c-FLIP could form DED chains/platforms at the DISC, ► The length of the DED chains is variable and depends on the stimulation strength ► Mathematical model supported by quantitative mass spectrometry and western blot
    Keywords: Biology
    ISSN: 1097-2765
    E-ISSN: 1097-4164
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  • 3
    Language: English
    In: PROTEOMICS, January 2009, Vol.9(2), pp.322-334
    Description: Olfactory sensory neurons expose to the inhaled air chemosensory cilia which bind odorants and operate as transduction organelles. Odorant receptors in the ciliary membrane activate a transduction cascade which uses cAMP and Ca for sensory signaling in the ciliary lumen. Although the canonical transduction pathway is well established, molecular components for more complex aspects of sensory transduction, like adaptation, regulation, and termination of the receptor response have not been systematically identified. Moreover, open questions in olfactory physiology include how the cilia exchange solutes with the surrounding mucus, assemble their highly polarized set of proteins, and cope with noxious substances in the ambient air. A specific ciliary proteome would promote research efforts in all of these fields. We have improved a method to detach cilia from rat olfactory sensory neurons and have isolated a preparation specifically enriched in ciliary membrane proteins. Using LC‐ESI‐MS/MS analysis, we identified 377 proteins which constitute the olfactory cilia proteome. These proteins represent a comprehensive data set for olfactory research since more than 80% can be attributed to the characteristic functions of olfactory sensory neurons and their cilia: signal processing, protein targeting, neurogenesis, solute transport, and cytoprotection. Organellar proteomics thus yielded decisive information about the diverse physiological functions of a sensory organelle.
    Keywords: Mass Spectrometry ; Olfactory Receptor Neurons ; Proteomic Analysis ; Sensory Cilia ; Signal Transduction
    ISSN: 1615-9853
    E-ISSN: 1615-9861
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  • 4
    Language: English
    In: European Journal of Pharmacology, 15 September 2012, Vol.691(1-3), pp.218-224
    Description: Human lung fibroblasts are a potential source of endothelin-1 (ET-1), a pro-fibrotic mediator. The present study explored possible muscarinic and β-adrenergic modulations of ET-1 expression in human lung fibroblasts. MRC-5 human lung fibroblasts were cultured. Expression of prepro-endothelin-1 (ppET-1) mRNA was determined by quantitative real time PCR. [ H]-Proline incorporation was determined as measure of collagen synthesis. The muscarinic agonist oxotremorine induced, in a tiotropium-sensitive manner, a three-fold increase in ppET-1 mRNA. The β -adrenoceptor agonist olodaterol caused a reduction of ppET-1 mRNA by 45%. Olodaterol also opposed the stimulatory effect of oxotremorine. The effect of olodaterol was mimicked by the protein kinase A agonist 6-Bnz-cAMP, whereas the Epac (exchange protein activated by cAMP) agonist 8-CPT-2′- -Me-cAMP was less effective. Transforming growth factor-β (TGF-β, 0.3 and 1 ng/ml) induced a three- and eight-fold increase in pp-ET-1 mRNA, respectively. Olodaterol opposed the effect of 0.3, but not that of 1 ng/ml TGF-β. Likewise, 6-Bnz-cAMP opposed the effect of 0.3, but not that of 1 ng/ml TGF-β. TGF-β inhibited β -adrenoceptor mRNA expression, maximally by 90%. Muscarinic agonist-induced stimulation of [ H]-proline incorporation was attenuated by the endothelin ET1 receptor antagonist bosentan. In conclusion, ET-1 expression in human lung fibroblasts is regulated by stimulatory muscarinic receptors and inhibitory β -adrenoceptors. Since muscarinic up-regulation of ET-1 contributes to pro-fibrotic effects of muscarinic stimuli, inhibition of ET-1 expression could contribute to long-term beneficial effects of long-acting β -adrenoceptor agonists and long-acting muscarinic antagonists. However, excessive exposure to TGF-β results in loss of β-adrenoceptor expression and function of its down-stream signaling.
    Keywords: Endothelin-1 ; Lung Fibroblasts ; Airway Remodelling ; Muscarinic Receptor ; Β-Adrenoceptor ; Transforming Growth Factor-Β ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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