Kriegsmann J.,MVZ for Histology |
Kriegsmann J.,Institute for Molecular Pathology |
Kriegsmann J.,Proteopath GmbH |
Kriegsmann M.,University of Heidelberg |
Casadonte R.,Proteopath GmbH
International Journal of Oncology | Year: 2015
Matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) is an evolving technique in cancer diagnostics and combines the advantages of mass spectrometry (proteomics), detection of numerous molecules, and spatial resolution in histological tissue sections and cytological preparations. This method allows the detection of proteins, peptides, lipids, carbohydrates or glycoconjugates and small molecules. Formalin-fixed paraffin-embedded tissue can also be investigated by IMS, thus, this method seems to be an ideal tool for cancer diagnostics and biomarker discovery. It may add information to the identification of tumor margins and tumor heterogeneity. The technique allows tumor typing, especially identification of the tumor of origin in metastatic tissue, as well as grading and may provide prognostic information. IMS is a valuable method for the identification of biomarkers and can complement histology, immunohistology and molecular pathology in various fields of histopathological diagnostics, especially with regard to identification and grading of tumors.
News Article | December 1, 2016
(Vienna, the 01.12.2016) It promises to be a simple and elegant strategy to heal diabetes type 1: Replacing the destroyed beta-cells in the bodies of patients with newly-produced insulin-secreting cells. For years, researchers around the globe tried various approaches with stem- or adult cells in order to induce this transformation. Their effort lead to a fundamental understanding of the molecular mechanisms involved in the development of beta cells - however, a compound capable of doing the trick was missing. Then a team coordinated by Stefan Kubicek, Group Leader at CeMM, eventually got a lead: In their latest study, published in Cell (DOI: 10.1016/j.cell.2016.11.010), they showed that artemisinins hit the bulls eye. With a specially designed, fully automated assay, they tested the effects of a representative library of approved drugs on cultured alpha cells and found the malaria drug to do the required job. "With our study, we could show that artemisinins change the epigenetic program of glucagon-producing alpha cells and induce profound alterations of their biochemical function", Stefan Kubicek explains. Alpha- and beta cells form together with at least three other highly specialized cell types the so-called islets of Langerhans in the pancreas, the body's control centers for the regulation of blood sugar. Insulin, the hormone produced by beta cells, signals to reduce blood glucose, while glucagon from alpha cells has the opposite effect. But those cells are flexible: Previous studies showed that alpha cells can replenish insulin producing cells following extreme beta cell loss. The epigenetic master regulator Arx was identified as the key molecular player in the transformation process. "Arx regulates many genes that are crucial for the functionality of an alpha cell," says Stefan Kubicek. "Preceding work of our collaborator, Patrick Collombat's team showed that a genetic knock out of Arx leads to a transformation of alpha cells into beta cells." This effect, however, was only observed in live model organisms - it was completely unknown if additional factors from the surrounding cells or even distant organs play a role. To exclude those factors, Kubicek's team together with the group of Jacob HecksherSorensen at Novo Nordisk designed special alpha and beta cell lines to analyze them isolated from their environment. They proved that loss of Arx is sufficient to confer alpha cell identity and does not depend on the body's influence. With those cell lines, the researchers at CeMM where now able to test their compound library and found artemisinins to have the same effect as an Arx loss. In close collaboration with research groups at CeMM lead by Christoph Bock and Giulio Superti-Furga as well as the group of Tibor Harkany at the Medical University of Vienna they managed to elucidate the molecular mode of action by which artemisinins reshape alpha cells: The compound binds to a protein called gephyrin, that activates GABA receptors, central switches of the cellular signaling. Subsequently, the change of countless biochemical reactions lead to the production of insulin. Another study by Patrick Collombat, published in the same issue of Cell, shows that in mouse models injections of GABA also lead to the transformation of alpha into beta cells, suggesting that both substances target the same mechanism. In addition to the cell line experiments, the effect of the malaria drug was also shown in model organisms: Stefan Kubicek´s team and their collaborators (Martin Distel, CCRI Wien; Dirk Meyer, Leopold-Franzens-Universität Innsbruck; Patrick Collombat, INSERM Nice; Physiogenex, Labege) observed an increased beta cell mass and improved blood sugar homeostasis in diabetic zebrafish, mice and rats upon artemisinin delivery. As the molecular targets for artemisinins in fish, rodents and humans are very similar, chances are high that the effect on alpha cells will also occur in humans. "Obviously, the long term effect of artemisinins needs to be tested," says Stefan Kubicek. "Especially the regenerative capacity of human alpha cells is yet unknown. Furthermore, the new beta cells must be protected from the immune system. But we are confident that the discovery of artemisinins and their mode of action can form the foundation for a completely new therapy of type 1 diabetes." The Study "Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity" is published in Cell on 1st of December 2016; DOI:10.1016/j.cell.2016.11.010. Funding: This work was partially funded by the Juvenile Diabetes Research Foundation (JDRF), the European Research Council (ERC), the Medical University of Vienna, the European Molecular Biology Organization (EMBO), the NovoNordisk Foundation, the European Commission FP7 Marie Sk?odowska-Curie Actions, the Austrian Science Fund (FWF), the Austrian Academy of Sciences (ÖAW); the INSERM AVENIR program; the INSERM, the FMR, the ANR/BMBF, LABEX SIGNALIFE, the Max-Planck-Society, Club Isatis, Mr. and Mrs. Dorato, Mr. and Mrs. Peter de Marffy-Mantuano, the Fondation Générale de Santé and the Foundation Schlumberger pour l'Education et la Recherche. Stefan Kubicek studied organic chemistry in Vienna and Zürich. He received his Ph.D. in Thomas Jenuwein's group at the Institute for Molecular Pathology (IMP) in Vienna followed by postdoctoral work with Stuart Schreiber at the Broad Institute of Harvard and MIT in the U.S. He joined CeMM in 2010. He is the Head of the Chemical Screening and Platform Austria for Chemical Biology (PLACEBO) and the Christian Doppler Laboratory for Chemical Epigenetics and Anti-Infectives. The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an interdisciplinary research institute committed to advancing the understanding of human diseases through basic and biomedical research. Located at the center of the Medical University of Vienna's campus, CeMM fosters a highly collaborative and interactive research mindset. Focusing on medically relevant questions, CeMM researchers concentrate on human biology and diseases like cancer and inflammation/immune disorders. In support of scientific pursuits and medical needs, CeMM provides access to cutting-edge technologies and has established a strategic interest in personalized medicine. Since 2005, Giulio Superti-Furga is the Scientific Director of CeMM. http://www. For further information please contact Mag. Wolfgang Däuble Media Relations Manager CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 1090 Vienna, Austria Phone +43-1/40160-70 057 Fax +43-1/40160-970 000 email@example.com http://www.
Neumann B.,MitoCheck Project Group |
Walter T.,MitoCheck Project Group |
Heriche J.-K.,Wellcome Trust Sanger Institute |
Heriche J.-K.,MitoCheck Project Group |
And 30 more authors.
Nature | Year: 2010
Despite our rapidly growing knowledge about the human genome, we do not know all of the genes required for some of the most basic functions of life. To start to fill this gap we developed a high-throughput phenotypic screening platform combining potent gene silencing by RNA interference, time-lapse microscopy and computational image processing. We carried out a genome-wide phenotypic profiling of each of the ∼21,000 human protein-coding genes by two-day live imaging of fluorescently labelled chromosomes. Phenotypes were scored quantitatively by computational image processing, which allowed us to identify hundreds of human genes involved in diverse biological functions including cell division, migration and survival. As part of the Mitocheck consortium, this study provides an in-depth analysis of cell division phenotypes and makes the entire high-content data set available as a resource to the community. © 2010 Macmillan Publishers Limited. All rights reserved.
Morandell S.,Innsbruck Medical University |
Morandell S.,Massachusetts Institute of Technology |
Grosstessner-Hain K.,Institute for Molecular Pathology |
Roitinger E.,Institute for Molecular Pathology |
And 10 more authors.
Proteomics | Year: 2010
Signaling networks regulate cellular responses to external stimuli through post-translational modifications such as protein phosphorylation. Phosphoproteomics facilitate the large-scale identification of kinase substrates. Yet, the characterization of critical connections within these networks and the identification of respective kinases remain the major analytical challenge. To address this problem, we present a novel approach for the identification of direct kinase substrates using chemical genetics in combination with quantitative phosphoproteomics. Quantitative identification of kinase substrates (QIKS) is a novel-screening platform developed for the proteome-wide substrate-analysis of specific kinases. Here, we aimed to identify substrates of mitogen-activated protein kinase/Erk kinase (Mek1), an essential kinase in the mitogen-activated protein kinase cascade. An ATP analog-sensitive mutant of Mek1 (Mek1-as) was incubated with a cell extract from Mek1 deficient cells. Phosphorylated proteins were analyzed by LC-MS/MS of IMAC-enriched phosphopeptides, labeled differentially for relative quantification. The identification of extracellular regulated kinase 1/2 as the sole cytoplasmic substrates of MEK1 validates the applicability of this approach and suggests that QIKS could be used to identify substrates of a wide variety of kinases. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.
Majewski I.J.,Walter and Eliza Hall Institute of Medical Research |
Ritchie M.E.,Walter and Eliza Hall Institute of Medical Research |
Phipson B.,Walter and Eliza Hall Institute of Medical Research |
Corbin J.,Walter and Eliza Hall Institute of Medical Research |
And 11 more authors.
Blood | Year: 2010
Polycomb group (PcG) proteins are transcriptional repressors with a central role in the establishment and maintenance of gene expression patterns during development. We have investigated the role of polycomb repressive complexes (PRCs) in hematopoietic stem cells (HSCs) and progenitor populations. We show that mice with loss of function mutations in PRC2 components display enhanced HSC/progenitor population activity, whereas mutations that disrupt PRC1 or pleiohomeotic repressive complex are associated with HSC/progenitor cell defects. Because the hierarchical model of PRC action would predict synergistic effects of PRC1 and PRC2 mutation, these opposing effects suggest this model does not hold true in HSC/progenitor cells. To investigate the molecular targets of each complex in HSC/progenitor cells, we measured genome-wide expression changes associated with PRC deficiency, and identified transcriptional networks that are differentially regulated by PRC1 and PRC2. These studies provide new insights into the mechanistic interplay between distinct PRCs and have important implications for approaching PcG proteins as therapeutic targets. © 2010 by The American Society of Hematology.