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183 results on '"H. Grunicke"'

3. Traffic tunnels – Development of a cross‐asset, reliability‐based life cycle management

Author

Andreas van Linn, Christian Stefan, Urs H. Grunicke, Lars Derek Mellert, and Alfred Weninger‐Vycudil

Subjects
Product life-cycle management, Risk analysis (engineering), Computer science, business.industry, Maintenance strategy, Asset management, Asset (economics), Geotechnical Engineering and Engineering Geology, business, Reliability (statistics), Civil and Structural Engineering, Application lifecycle management
Published
2020

4. Pre-stressed tunnel lining - pushing traditional concepts to new frontiers / Neue Grenzen für passiv vorgespannte Druckstollenauskleidungen

Author

Mladen Ristić and Urs H. Grunicke

Subjects
Pre stressing, Engineering, business.industry, Mechanical engineering, Horizontal stress, Geotechnical Engineering and Engineering Geology, business, Geomorphology, Civil and Structural Engineering
Abstract

Pressure tunnels with pre-stressed concrete linings are recognised as state-of-the-art technology. Numerous pre-stressed concrete linings, featuring diameters of up to 6 m, have been successfully implemented over the last few decades. This paper on the Niagara Tunnel Facility Project (NTFP) illustrates how the concept of passive pre-stressing can be further developed for application in increasingly complex geometrical and geotechnical boundary conditions. The diversion tunnel with an excavation diameter of 14.4 m was advanced in horizontal layers of sedimentary rock, which are characterised by a wide range of strengths and anisotropic stiffnesses as well as by pronounced time-dependent deformation behaviour. The in-situ stress field is marked by an exceptionally high horizontal stress, which s several times greater than the overburden pressure. The ground has a considerable swelling potential and is highly aggressive to concrete. This combination of difficult geotechnical conditions and unusual structural dimensions poses an unprecedented challenge to the designers with respect to both the design of the pre-stressed final lining and the planning of the grouting works. The long-term behaviour is modelled with the help of higher-order creep and shrinkage laws, which are calibrated based on trials and measurements. Druckstollen mit vorgespannter Betonauskleidung stellen einen anerkannten Stand der Technik dar. Fur passiv vorgespannte Druckstollenauskleidungen liegt eine Vielzahl an langjahrigen Erfahrungen fur Durchmesser bis 6 m vor. Dieser Beitrag erlautert anhand des Beispiels des Niagara Tunnel Facility Projects (NTFP), wie das Konzept der passiven Vorspannung auf geometrisch wie geotechnisch ungewohnliche Rahmenbedingungen erweitert werden kann. Der Umleitungstunnel mit einem Ausbruchdurchmesser von 14,4 m wurde in einer horizontalen Wechselfolge von Sedimentgesteinen vorgetrieben, die eine grose Bandbreite an Festigkeiten und anisotropen Steifigkeiten sowie ein ausgepragtes zeitabhangiges Verformungsverhalten aufweisen. Das Primarspannungsfeld ist charakterisiert durch ungewohnlich hohe Horizontalspannungen, die ein Vielfaches des Uberlagerungsdrucks betragen. Es besteht ein ausgepragtes Quellpotenzial sowie ein stark betonaggressives Milieu. Die Kombination aus schwierigen geotechnischen Verhaltnissen mit ungewohnlichen Bauwerksdimensionen, stellt den Entwurf der vorgespannten Innenschale vor eine bislang unbekannte Herausforderung hinsichtlich Dimensionierung und Planung der Verpressarbeiten. Das Langzeitverhalten wird mithilfe hoherwertiger Kriech- und Schwindgesetze abgebildet, die anhand von Versuchen und Messungen kalibriert wurden.

Published
2012

5. Coordinated Regulation of Ras-, Rac-, and Ca2+-Dependent Signaling Pathways

Author

H. Grunicke

Subjects
Chemistry, GTPase, SH3 domain, rac GTP-Binding Proteins, Cell biology, Rac GTP-Binding Proteins, Eukaryotic Cells, ras Proteins, Genetics, Animals, Guanine Nucleotide Exchange Factors, Humans, Calcium, NCK1, Calcium Signaling, Guanosine Triphosphate, Guanine nucleotide exchange factor, Signal transduction, Molecular Biology, Signal Transduction, Calcium signaling, G protein-coupled receptor
Abstract

Stimulation of cells by a broad variety of agonists results in a coordinated activation of Ca2+-, Ras-, and Rac-dependent pathways, which have to synergize to yield the corresponding biological response. This synergy requires a dense net of mutually positive and negative regulatory mechanisms. These include Ca2+-mediated activation of guanine nucleotide exchange proteins, resulting in increased levels of GTP-charged Ras and/or Rac or inactivation of small GTPases by Ca2+-mediated activation of GTPase-activating enzymes. Likewise, Ras as well as Rac control regulatory mechanisms, resulting in increased or diminished levels of cytosolic-free Ca2+. The biochemical mechanisms underlying these effects are discussed, with special reference to regulation of Ca2+ signaling by Ras and Rac.

Published
2009

6. Regulation of calcium signalling by the small GTP-binding proteins Ras and Rac1

Author

Irene Wede, Kukka Strese, Georg Hechenberger, H. Grunicke, K. Maly, Wolfgang Doppler, and Ingeborg Tinhofer

Subjects
rac1 GTP-Binding Protein, Cancer Research, Chemistry, RAC1, Cell biology, ErbB Receptors, Mice, GTP-binding protein regulators, Amino Acid Substitution, Anti-apoptotic Ras signalling cascade, Calcium-binding protein, NIH 3T3 Cells, ras Proteins, Genetics, Animals, Molecular Medicine, Calcium, Cattle, Calcium Signaling, Molecular Biology, Calcium signaling
Published
2007

7. Molecular basis of targeted chemotherapy: Novel concepts with special reference to the treatment of Hodgkin’s disease

Author

H. H. Grunicke

Subjects
Antineoplastic Agents, Apoptosis, Signal transduction inhibitor, immune system diseases, hemic and lymphatic diseases, medicine, Humans, Reed-Sternberg Cells, Protein Kinase C, Protein kinase C, Janus kinase 2, Oncogene, biology, business.industry, Hematology, medicine.disease, Hodgkin Disease, Genes, bcl-2, Lymphoma, Genes, ras, Oncology, Reed–Sternberg cell, Cancer research, biology.protein, Signal transduction, Janus kinase, business, Signal Transduction, Transcription Factors
Abstract

Concepts for the treatment of Hodgkin's lymphomas based on novel insights of the molecular mechanisms responsible for the maintenance of the transformed phenotype of Reed-Sternberg cells, their proliferation and sensitivity to radiation and anti-tumor agents are discussed. The potentials of some recently developed new signal transduction inhibitors for the treatment of Hodgkin's lymphomas are discussed in greater detail and comprise agents directed against Janus kinase 2 (JAK 2); Signal Transducers and Activators of Transcription (STAT factors); agents directed against SH 2-domains: the fes/fps oncogene, Ras; protein kinase C (PKC) isotypes and means of inducing radiation or drug-induced apoptosis.

Published
1998

8. Resistance to the new anti-cancer phospholipid ilmofosine (BM 41 440)

Author

H. Grunicke, Johann Hofmann, I. Utz, William T. Beck, M. Rybczynska, S Hofer, D. B. J. Herrmann, and M. Spitaler

Subjects
Dihydropyridines, Cancer Research, medicine.medical_specialty, Time Factors, Antineoplastic Agents, HeLa, Internal medicine, Tumor Cells, Cultured, medicine, Humans, Doxorubicin, ATP Binding Cassette Transporter, Subfamily B, Member 1, P-glycoprotein, Antibiotics, Antineoplastic, Dose-Response Relationship, Drug, biology, Topoisomerase, Phospholipid Ethers, Transfection, biology.organism_classification, Molecular biology, Drug Resistance, Multiple, Multiple drug resistance, Cell Transformation, Neoplastic, Endocrinology, Oncology, Epidermoid carcinoma, Drug Resistance, Neoplasm, Cell culture, biology.protein, Genes, MDR, Cell Division, HeLa Cells, Research Article, medicine.drug
Abstract

The thioether phospholipid ilmofosine (BM 41 440) is a new anti-cancer drug presently undergoing phase II clinical trials. Because resistance to anti-tumour drugs is a major problem in cancer treatment, we investigated the resistance of different cell lines to this compound. Here we report that the multidrug-resistant cell lines MCF7/ADR, CCRFNCR1000, CCRF/ADR500, CEM/VLB100 and HeLa cell lines transfected with a wild-type and mutated (gly/val185) multidrug resistance 1 gene (MDR1) are cross-resistant to ilmofosine compared with the sensitive parental cell lines. In CEMNM-1 cells, in which the resistance is associated with an altered topoisomerase II gene, no cross-resistance to ilmofosine was observed. Ilmofosine is not capable of modulating multidrug resistance and neither does it reduce the labelling of the P-glycoprotein (P-gp) by azidopine nor alter ATPase activity significantly. The resistance to ilmofosine in multidrug-resistant CCRF/VCR1000 cells cannot be reversed by the potent multidrug resistance modifier dexniguldipine-HCI (B8509-035). A tenfold excess of ilmofosine does not prevent the MDR-modulating effect of dexniguldipine-HCl. Treatment of cells with ilmofosine does not alter the levels of MDR1 mRNA. Long-term treatment of an ilmofosine-resistant Meth A subline with the drug does not induce multidrug resistance, indicating that ilmofosine does not increase the level of P-gp. Determination of the MDR2 mRNA levels in the cells revealed that the resistance pattern to ilmofosine is not correlated with the expression of this gene. It is concluded, therefore, that multidrug-resistant cells are cross-resistant to ilmofosine and that the compound is not a substrate of Pgp. No association between the expression of the MDR2-encoded P-gp and resistance to ilmofosine was observed. It is supposed that MDR1-associated alterations in membrane lipids cause resistance to ilmofosine. Images Figure 4 Figure 8 Figure 9

Published
1997

9. Effects of the selective bisindolylmaleimide protein kinase C inhibitor GF 109203X on P-glycoprotein-mediated multidrug resistance

Author

I. Utz, Kurt Prof Dr Klemm, C. Schachtele, Florian Überall, Volker Gekeler, Rainer Boer, Johann Hofmann, W Ise, C Schubert, H. Grunicke, and K.H. Sanders

Subjects
Azides, Dihydropyridines, Cancer Research, Bisindolylmaleimide, Indoles, Gene Expression, PKC alpha, Rhodamine 123, Isozyme, Maleimides, Mice, chemistry.chemical_compound, Animals, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, Enzyme Inhibitors, Phosphorylation, Protein Kinase C, Protein kinase C, P-glycoprotein, biology, 3T3 Cells, Drug Resistance, Multiple, Multiple drug resistance, Verapamil, Oncology, chemistry, Biochemistry, Enzyme inhibitor, biology.protein, Research Article
Abstract

Inhibition of protein kinase C (PKC) is discussed as a new approach for overcoming multidrug resistance (MDR) in cancer chemotherapy. For evaluation of this concept we applied the bisindolylmaleimide GF 109203X, which shows a highly selective inhibition of PKC isozymes alpha, beta 1, beta 2, gamma, delta and epsilon in vitro. The efficacy of this compound in modulation of MDR was examined using several P-glycoprotein (P-gp)-overexpressing cell lines including a MDR1-transfected HeLa clone, and was compared with the activities of dexniguldipine-HCI (DNIG) and dexverapamil-HC1 (DVER), both of which essentially act via binding to P-gp. As PKC alpha has been suggested to play a major role in P-gp-mediated MDR, cell lines exhibiting different expression levels of this PKC isozyme were chosen. On crude PKC preparations or in a cellular assay using a cfos(-711)CAT-transfected NIH 3T3 clone, the inhibitory qualities of the bisindolylmaleimide at submicromolar concentrations were demonstrated. At up 1 microM final concentrations of the PKC inhibitor GF 109203X, a concentration at which many PKC isozymes should be blocked substantially, no cytotoxic or MDR-reversing effects whatsoever were seen, as monitored by 72 h tetrazolium-based colorimetric MTT assays or a 90 min rhodamine 123 accumulation assay. Moreover, depletion of PKC alpha by phorbol ester in HeLa-MDR1 transfectants had no influence on rhodamine 123 accumulation after 24 or 48 h. MDR reversal activity of GF 109203X was seen at higher final drug concentrations, however. Remarkably, [3H]vinblastine-sulphate binding competition experiments using P-gp-containing crude membrane preparations demonstrated similar dose dependencies as found for MDR reversion by the three modulators, i.e. decreasing efficacy in the series dexniguldipine-HCl > dexverapamil-HCl > GF 109203X. Similar interaction with the P-gp in the micromolar concentration range was revealed by competition of GF 109203X with photoincorporation of [3H]azidopine into P-gp-containing crude membrane preparations. No significant effect of the PKC inhibitor on MDR1 expression was seen, which was examined by cDNA-PCR. Thus, the bisindolylmaleimide GF 109203X probably influences MDR mostly via direct binding to P-gp. Our work identifies the bisindolylmaleimide GF 109203X as a new type of drug interacting with P-gp directly, but does not support the concept of a major contribution of PKC to a P-gp-associated MDR, at least using the particular cellular model systems and the selective, albeit general, PKC inhibitor GF 109203X. Images Figure 1 Figure 3 Figure 10

Published
1996

10. Transforming potentials of epidermal growth factor and nerve growth factor receptors inversely correlate with their phospholipase C gamma affinity and signal activation

Author

I Tinhofer, A Obermeier, H H Grunicke, and Axel Ullrich

Subjects
General Immunology and Microbiology, biology, General Neuroscience, Inositol trisphosphate, Phospholipase C gamma, Molecular biology, General Biochemistry, Genetics and Molecular Biology, Receptor tyrosine kinase, Cell biology, chemistry.chemical_compound, chemistry, Growth factor receptor, Epidermal growth factor, Trk receptor, biology.protein, Epidermal growth factor receptor, Molecular Biology, Proto-oncogene tyrosine-protein kinase Src
Abstract

The exchange of nerve growth factor receptor/Trk and epidermal growth factor receptor (EGFR) phospholipase C gamma (PLC gamma) binding sites resulted in the transfer of their distinct affinities for this Src homology 2 domain-containing protein. Relative to wild-type EGFR, the PLC gamma affinity increase of the EGFR switch mutant EGFR.X enhanced its inositol trisphosphate (IP3) and calcium signals and resulted in a more sustained mitogen-activated protein (MAP) kinase activation and accelerated receptor dephosphorylation. In parallel, EGFR.X exhibited a significantly decreased mitogenic and transforming potential in NIH 3T3 cells. Conversely, the transfer of the EGFR PLC gamma binding site into the Trk cytoplasmic domain context impaired the IP3/calcium signal and attenuated the MAP kinase activation and receptor dephosphorylation, but resulted in an enhancement of the ETR.X exchange mutant mitogenic and oncogenic capacity. Our findings establish the significance of PLC gamma affinity for signal definition, the role of this receptor tyrosine kinase substrate as a negative feedback regulator and the importance of this regulatory function for mitogenesis and its disturbance in oncogenic aberrations.

Published
1996

11. 8th International AEK Symposium of the Division of Experimental Cancer Research of the German Cancer Society

Author

H-E Gabbert, K. Bosslet, Hartmut M. Rabes, M. F. Rajewsky, H. Grunicke, G. Eisenbrand, Werner K. Lutz, Martin R. Schneider, G. Bornkamm, P von Hoegen, and G. Brandner

Subjects
German, Cancer Research, medicine.medical_specialty, Oncology, business.industry, Family medicine, medicine, language, Cancer, General Medicine, medicine.disease, business, language.human_language
Published
1995

14. Biochemie der Ernährung

Author

H. Grunicke

Abstract

Belebte Materie zeichnet sich thermodynamisch durch einen hohen Ordnungsgrad, d. h. niedrige Entropie aus. Die Aufrechterhaltung derartiger Ordnungszustande ist nur bei dauernder Energiezufuhr moglich. Daraus folgt, dass schon unsere blose korperliche Existenz in Abwesenheit zusatzlicher Arbeitsleistungen energieabhangig ist. Der tatsachliche Energiebedarf des menschlichen Organismus geht schon unter Grundumsatzbedingungen, nicht zuletzt wegen der Bedurfnisse der stoffwechselaktiven Organe, Zentralnervensystem, Herz, Leber, Niere, weit uber die zum Strukturerhalt notwendige Energie hinaus und wird durch motorische Aktivitat und Stress zusatzlich gesteigert.

Published
2010

15. Scientific Proceedings Second International Symposium on Cytostatic Drug Resistance

Author

Bridget T. Hill, L. K. Hosking, S. McClean, S. A. Shellard, W. C. M. Dempke, R. D. H. Whelan, M. Sehested, E. Friche, E. J. F. Demant, P. B. Jensen, B. P. Kopnin, B. Wolf, A. Seidel, M. Nickelsen, I. Brandt, G. Heinemann, M. Dietel, S. Bremer, T. Hoof, B. Tümmler, H. J. Broxterman, C. H. M. Versantvoort, C. M. Kuiper, N. Feller, G. J. Schuurhuis, J. Lankelma, S. Gupta, T. Tsuruo, C. Kim, S. Gollapudi, A. Bittl, M. Nap, W. Jäger, B. Lathan, N. Lang, N. T. Raikhlin, A. G. Perevozchikov, J. L. Volodina, T. Licht, H. H. Fiebig, K. J. Bross, F. Herrmann, R. Mertelsmann, I. Bashir, K. Sikora, C. S. Foster, M. Castagna, P. Viacava, M. Cianfrigliao, A. Favati, P. Collecchi, M. A. Caligo, G. Cipollini, G. Bevilacqua, D. Schrenk, T. W. Gant, J. A. Silverman, S. S. Thorgeirsson, A. Harstrick, Z. G. Zhang, H. J. Schmoll, Y. Rustum, M. Mitze, T. Beck, W. Weikel, C. Brumm, P. G. Knapstein, T. McDonald, P. Gardner, N. Kang, S. A. M. van der Heyden, H. J. Elst, U. Stein, B. Jandrig, H. Krause, P. Schmidt-Peter, J. Frege, V. Wunderlich, E. Boven, C. K. van Kalken, H. M. Pinedo, W. Gebauer, E. Fallgren-Gebauer, M. Diete, T. Wagner, M. R. Müller, K. Lennartz, H. R. Nowrousian, S. Seeber, A. A. Shtil, A. R. Kazarov, A. V. Gudkov, A. A. Stavrovskaya, F. H. Djuraeva, T. P. Stromskaya, A. Noller, G. Frese, M. Neumann, A. Wilisch, H. Probst, V. Gekeler, R. Handgretinger, H. Schmidt, C. P. Muller, R. Dopfer, T. Klingebiel, D. Niethammer, S. Weger, H. Diddens, E. Daumiller, A. Bunge, R. Lilischkis, A. Salmassi, M. Kopun, H. Scherthan, C. Granzow, I. Leuschner, D. Schmidt, H. Hoffmann, D. Harms, G. V. Scagliotli, E. Leonardo, S. Cappia, G. Esposito, M. Tombesi, M. Cianfriglia, G. V. Esposito, N. Merendino, M. Viora, M. Caserta, E. Tritarelli, E. Rocca, G. Boccoli, P. Samoggia, C. Fossati, U. Testa, C. Peschle, J. L. Darling, S. M. Ashmore, D. C. Peterson, D. G. T. Thomas, R. A. Kramer, R. Stanlunas, T. Summerhayes, T. Lion, R. H. Shoemaker, L. Wu, A. Smythe, M. R. Boyd, W. T. Beck, M. K. Danks, J. S. Wolverton, M. Chen, B. Y. Bugg, D. P. Suttle, C. V. Catapano, D. J. Fernandes, F. Gieseler, F. Boege, R. Erttmann, H. Arps, L. Zwelling, K. Wilms, H. Biersack, G. J. L. Kaspers, R. Pieters, E. Klumper, F. C. de Waal, E. R. van Wering, A. J. P. Veerman, C. A. Schmidt, F. Lorenz, A. Schäfer, A. Kirsch, W. Siegert, D. Huhn, W. E. Simon, G. Siebert, M. Schneider, M. Oettling, A. Reymann, R. Entmann, S. Schmidt, C. Woermann, C. Windmeier, I. Herzig, B. Schaefer, H. J. Heidebrecht, H. H. Wacker, H. Künnemann, Th. H. M. van Heijningen, M. L. Slovak, J. P. A. Baak, K. Steidtmann, A. -M. J. Fichtinger-Schepman, B. I. Hill, K. J. Scanlon, W. J. Zeller, G. Chen, J. A. Gietema, E. G. E de Vries, D.Th Sleijfer, P. H. B. Willemse, H. J. Guchelaar, D. R. A. Uges, P. Aulenbacher, R. Voegeli, N. H. Mulder, C. Skrezek, H. Bertermann, H. Eichholtz-Wirth, R. Born, H. Bier, M. Koch, G. Bernhardt, K. Hählen, H. Reile, C. H. van Zantwijk, T. Görögh, B. Lippert, J. A. Werner, J. E. Eickbohm, G. H. Mickiseh, M. M. Gottesman, I. Pastan, J. Hofmann, A. Wolf, M. Spitaler, G. Bock, H. Grunicke, H. Ponstingl, I. Roth, C. Dörner, G. Looft, G. J. Ossenkoppele, G. L. Scheffer, G. Atassi, A. Pierre, L. Kraus, S. Leonce, G. Regnier, A. Dhainaut, M. Stöhr, C. Rohlff, R. I. Glazer, Y. S. Cho-Chung, V. Höllt, M. Kouba, G. Vogt, H. Allmeier, N. I. Nissen, S. Cros, N. Guilbaud, T. Dunn, M. Berlion, J. P. Bizzari, A. M. Messing, A. Matuschek, I. Mutter, J. C. W. Kiwit, L. Bastian, P. E. Goretzki, A. Frilling, D. Simon, H. D. Röher, A. Reichle, F. Altmayr, J. Rastetter, C. Erbil, G. Jaques, M. Maasberg, K. Havemann, K. Häußermann, H. -J. Heidebrecht, W. Van de Vrie, E. E. O. Gheuens, N. M. C. Durante, E. A. De Bruijn, R. L. Marquet, A. T. Van Oosterom, A. M. M. Eggermont, M. W. Stow, S. E. Vickers, J. R. Warr, E. Roller, M. Eichelbaum, B. Klumpp, J. Krause, K. Schumacher, S. Hörner, A. Laßmann, U. Traugott, E. Schlick, D. Bürkle, BW Futscher, AF List, WS Dalton, E. Ladda, K. Bühl, A. Weimer, C. Eser, K. Hamprecht, K. P. Schalk, C. Jackisch, B. Brandt, M. Blum, F. Louwen, K. Schulz, J. P. Hanker, U. Rüther, A. Schmidt, H. A. G. Müller, C. Nunnensiek, H. Bader, F. Eisenberger, P. Jipp, B. Niethammer, C. Muller, V. Ling, F. Joncourt, S. Redmond, K. Buser, M. Fey, A. Tobler, K. Brunner, A. Gratwohl, T. Cerrry, V. Nuessler, R. Pelka-Fleischer, C. Nerl, B. Beckert, W. Wilmanns, S. Hegewisch-Becker, M. Fliegner, A. Zander, D. K. Hossfeld, J. Blanz, K. Mewes, G. Ehninger, K. -P. Zeller, H. Schuldes, G. Herrmann, W. Boeckmann, R. Schroeder, D. Jonas, K. -H. Zurborn, H. D. Bruhn, L. Uharek, B. Glass, W. Gassmann, H. Loeffler, W. Mueller-Ruohholtz, W. Mueller-Ruchholtz, K. Jaquet, H. Kreipe, J. Felgner, H. J. Radzun, M. R. Parwaresch, EA Kogan, NN Mazurenko, SM Sekamova, H. Wolf, K. Röhe, K. Wilkens, M. Clausen, E. Henze, J. van der Bosch, S. Rüller, M. Schlaak, U. Köhl, D. Schwabe, E. Rohrbach, E. Montag, S. Bauer, J. Cinatl, I. Cinatl, M. Mainke, H. Geiss, B. Kornhuber, H. Juhl, H. Stritzel, H. Kalhoff, W. Schniegel, T. Menke, B. Pröbsting, P. Schulze-Westhoff, J. Boos, J. Weidner, N. Wedemeyer, K. Wiedorn, Y. Ueda, S. Blasius, P. Wuisman, W. Böcker, A. Roessner, B. Dockhorn-Dworniczak, D. Ramm, J. Knebel, W. Sass, M. Aufderheide, and J. Seifert

Subjects
Cancer Research, medicine.medical_specialty, Oncology, business.industry, medicine, General Medicine, Drug resistance, Pharmacology, Intensive care medicine, business
Published
1991

16. Radiation-induced activation of transcription factors in mammalian cells

Author

Peter Herrlich, M Krämer, E Kunz, Helmut Ponta, B. Stein, H Loferer, H H Grunicke, Harald König, Sabine Mai, and Hans J. Rahmsdorf

Subjects
Radiation, DNA Repair, Transcription, Genetic, biology, General transcription factor, Response element, Biophysics, RNA polymerase II, E-box, Promoter, Molecular biology, Enhancer Elements, Genetic, Gene Expression Regulation, Sp3 transcription factor, biology.protein, Animals, Enhancer, Protein Processing, Post-Translational, Transcription factor, DNA Damage, Signal Transduction, Transcription Factors, General Environmental Science
Abstract

In mammalian cells radiation induces the enhanced transcription of several genes. The cis acting elements in the control region of inducible genes have been delimited by site directed mutagenesis. Several different elements have been found in different genes. They do not only activate gene transcription in response to radiation but also in response to growth factors and to tumor promoter phorbol esters. The transcription factors binding to these elements are present also in non-irradiated cells, but their DNA binding activity and their transactivating capability is increased upon irradiation. The signal chain linking the primary radiation-induced signal (damaged DNA) to the activation of transcription factors involves the action of (a) protein kinase(s).

Published
1990

17. Abstract of the 68th Meeting (Spring Meeting) 6–9 March 1990, Heidelberg

Author

B. Sakmann, J. Schrader, B. Brenner, H. Murer, J. Boeckh, H. O. Handwerker, P. HonerjÄger, M. Dugas, G. Wang, A. DeLuca, H. Brinkmeier, B. Fakler, T. Pröbstle, R. Rüdel, J. -A. Pohl, H. Meves, B. Kroll, S. Bremer, B. Tümmler, E. Frömter, J. S. Schwegler, W. Steigner, S. Silbernagl, Michael Pusch, P. Niemann, J. Schmidtmayer, W. Ulbricht, G. Hansen, U. Lönnendonker, B. Neumcke, R. Eickhorn, D. Hornung, H. Antoni, R. Penner, E. Neher, H. Takeshima, S. Nishimura, S. Numa, W. Melzer, D. Feldmeyer, B. Pohl, P. Zöllner, T. H. Müller, D. Swandulla, U Misgeld, V. Ya. Ganitkevich, G. Isenberg, A. Cavalié, T. J. A. Allen, W. Trautwein, Siegried Pelzer, Yaroslav M. Shuba, Tatsuya Asai, Wolfgang Trautwein, Arthur M. Brown, Lutz Birnbauner, Terence F. McDonald, Dieter Pelzer, R. Eckert, J. Hescheler, W. Rosenthal, S. Offermann, D. Krautwurst, G. Schultz, Helmut Kettenmahn, J. Trotter, Alexe J N. Verkhratsky, Alexej N. Savtchenko, Alexej N. Verkhratsky, A. Schiefer, U. Klöckner, L. D. Partridge, S. SchÄfer, P. Jonas, D. S. Koh, K. Kampe, M. Hermsteiner, W. Vogel, C. K. Bauer, J. R. Schwarz, R. H. A. Fink, E. Wettwer, R. Weik, E. Schlatter, M. Bleich, M. Granitzer, T. Leal, W. Nagel, J. Crabbé, F. Lang, E. Kahn, F. Friedrich, M. Paulmichl, M. Hammerer, K. Maly, H. Grunicke, T. Böhm, B. Nilius, H. Gögelein, D. Dahlem, H. Weiss, S. Waldegger, E. Woell, R. Paulmichl, J. P. Ruppersberg, K. H. Schröter, M. Stocker, O. Pongs, R. Wittka, G. Boheim, R Lichtinghagen, C. K. Augustine, W. Stühmer, Dorothe Hoppe, D. Hoppe, K. E. Zittlau, C. Walther, H. Hatt, C. Franke, S. Quasthoff, E. Wischmeyer, H. Jockusch, M. Friedrich, K. Benndorf, G. Bollmann, Hj. Hirche, F. Hollunder-Reese, M. Mohrmann, R. Greger, S. Weber-Schürholz, T. Schürholz, M. Akabas, D. Landry, Q. Al-Awqati, A. H. Guse, G. Gercken, W. Meyerhof, H. -J. Westphale, U. Kerstins, H. Oberleithner, M. Tilmann, K. Kunzelmann, T. Klitsch, D. Siemen, A. Draguhn, T. A. Verdoorn, D. B. Pritchett, P. H. Seeburg, P. Malherbe, H. Möhler, J. Dudel, P. Stern, F. Zufall, J. Rosenheimer, D. O. Smith, R. Dörner, K. Ballanyi, W. -R. Schlue, B. Kalthof, L. Pott, C. Busch, T. Konno, M. Stenql, Ch. Reinhardt, H. Kaiser, R. Baumann, M. Wilimzig, R. Eichenlaub, E. Neumann, V. Lessmann, K. Gottmann, I. D. Dietzel, B. U. Keller, Y. Yaari, A. Konnerth, K. H. Backus, T. Giller, F. Knoflach, P. Pflimlin, G. Trübe, G. von Blankenfeld, S. Ymer, H. Sontheimer, M. Ewert, H. Kettenmann, R. Schneggenburger, D. Paschke, D. F. Hülser, J. Ubl, H. A. Kolb, J. Ströttchen, S. Boheim, F. Wehner, D. Guth, R. K. H. Kinne, H. R. Polder, D. Bödeker, Susanne Hoppe, H. Höller, W. Hampe, H. Ruf, I. Schulz, M. Dehlinger-Kremer, T. Ozawa, L. Vasilets, G. Schmalzing, K. MÄdefessel, H. Biel, W. Schwarz, B. C. Burckhardt, N. Stallmach, H. MairbÄurl, J. F. Hoffman, E. Schömig, A. Heuner, B. O. Göbel, W. Siffert, A. Butke, G. Hoffmann, M. -K. Meyer zu Brickwedde, H. Vetter, R. Düsing, D. Rosskopf, U. Osswald, J. Steffgen, H. Koepsell, H. Martens, M. Rübbelke, G. GÄbel, J. Arens, J. Stabel, Y. Fischer, J. Thomas, H. Rose, H. Kammermeier, Thomas Munsch, Joachim W. Deitmer, B. Engelmann, J. Duhm, D. Gunzel, S. Galler, H. Fischer, W. Clauss, W. Van Driessche, A Köckerling, JD Schulzke, D Sorgenfrei, M Fromm, B. Simon, V. Ganapathy, F. H. Leibach, G. Burckhardt, R. Krattenmacher, Rosita Voigt, S. Dietrich, A. Leyssens, S. L. Zhang, R. Weltens, P. Steels, B. Hoffmann, M. Heinz, B. Habura, A. Dörge, G. Rechkemmer, W. von Engelhardt, O. StrauB, M. Wiederholt, D. -G. Margineanu, K. M. Kreusel, M. Fromm, U. Lempart, D. Sorgenfrei, U. Hegel, A. J. Augustin, R. . Goldstein, E. Purucker, J. Lutz, B. Illek, K -P. Thiele, JS. Schwealer, J. Dittmer, C. Bauer, K. -U. Eckardt, R. Neumann, A. Kurtz, H. Fromm, J. D. Schulzke, P. Clausen, A. Krohn, S. Lüderitz, K. Hierholzer, U. Kersting, L. Woinowski, R. Gro\mann, X. U. Bin, F. Ellendorff, R. Nitschke, U. Fröbe, H. Scholz, R. della Bruna, H. Ehmke, P. B. Persson, M. Seyfarth, H. R. Kirchheim, M. S. Dietrich, N. Parekh, M. Steinhausen, C. P. Bührle, R. Nobiling, K. J. Ullrich, G. Rumrich, S. Klöss, F. Papavassiliou, J. Hoyer, C. Schmitt, A. Jungwirth, M. Ritter, H. J. Westphale, C. Bevan, C. Theiss, Liliana Denek, Johann S. Schwegler, Roland SchÄfer, Albert J. Augustin, August Heidland, B. Nafz, A. Just, M. Steidl, G. Pinggera, R. Gerstberger, H. Schütz, E. Simon, E. Lohrmann, B. Masereel, J. Delarge, H. J. Lang, H. C. Englert, D. Caliebe, M. Mályusz, P. Wrigge, G. Gronow, N. Klause, H. Zinnert, H. Fagel, W. Jelkmann, Ch. Weiss, R. Keil, W. Schmidt, C. Kröger, E. G. Brabant, A. Hilgendorf, S. Strauch, F. Lane, A. Prick, N. Golenhofen, S. Mildenberger, B. Flemming, D. Roloff, T. Wronski, G. Drews, A. Debuyser, J. C. Henquin, M. B. Jackson, S. A. DeRiemer, A. Schmid, S. Schnefel, A. Pröfrock, K. -D. Hinsch, J. Milz, G. Lamprecht, U. Seidler, W. Silen, O. Aziz, W. Reschke, G. Fischer, N. De Decker, T. Hayes, G. Coast, E. Van Kerkhove, F. von zur Mühlen, F. Eckstein, U Hegel, CJ Bentzel, EO Riecken, C. Siemer, P. Rothenpieler, E. Smith, K. R. Lutnicki, J. T. Wróbel, A. Ledwożyw, E. PietraŚ, S. Sender, Klaus D. Jürgens, T. Kleinschmidt, F. Werkmeister, H. Kiwull-Schöne, P. Kiwull, J. Vahle, M. Ott, R. E. Zimmermann, J. G. Elsing, D. Million, P. Zillner, M. Thiel, H. Bardenheuer, K. Peter, J. Fandrey, C. P. Siegers, H. Rupp, V. Elimban, N. S. Dhalla, I. Morano, B. Agostini, M. Mühleisen, W. F. H. M. Mommaerts, K. Ono, M. Wussling, W. Schenk, W. Boldt, P. Lipp, K. Schüttler, G. Szymanski, M. F. Wendt-Gallitelli, J. W. Herzig, H. Depersin, G. Grupp, I. Grupp, H. G. Glitsch, H. Pusch, Ch. Zylka, M. Brāndle, R. Jacob, T. Stein, W. Isselhard, J. Sturz, T. Minor, P. Wingenfeld, B. Siegmund, T. Klietz, P. Schwartz, H. M. Piper, Christa Linder, Stefan SchÄfer, Gerd Heusch, B. F. Becker, N. Reinholz, P. Raschke, B. Leipert, E. Gerlach, B. Dierberger, R. W. Gülch, M. Leverkus, T. Mitsuiye, U. Pohl, S. Y. Wang, R. Meyer, H. G. Haas, H. Ph Christmann, Th Dörner, D. Hock, R. Hertel, M. Gagelmann, W. G. Forssmann, W. J. Leijendekker, G. Kissling, H. Michel, A. Goetz, M. Freya, G. Fleckenstein-Grün, Jochen D. Schipke, Yasuhiko Harasawa, Seiryo Sugiura, Joe Alexander, Daniel Burkhoff, L. Kling, B. Müller-Beckmann, M. Schroth, G. Sponer, E. Böhm, K. Strein, A. Dorszewski, G. Arnold, G. K. Pike, D. J. Bryant, M. L. Roberts, R. H. Fink, Ch. Ross, A. Skyschally, R. Schulz, C. Linder, G. Heusch, J. D. Schipke, D. Burkhoff, J. Alexander, F. Gollnick, Kh. Peter, R. Franken-Weyers, M. M. Borst, A. Deussen, S. Pöpping, H. Hose, K. H. Strotmann, B. Lukascek, T. Karnath, K. Güttier, W. Klaus, K. Haverkampf, M. Guhlmann, S. Schmidt-Ott, U. Heuschen, G. Mall, G. Pfitzer, J. Rösch, A. Arner, J. C. Rüegg, K. Kröger, V. ThÄmer, Thomas Ehring, Volker ThÄmer, B. D. Guth, Ph A. Schnabel, A. Schmiedl, M. M. Gebhard, J. Richter, H. J. Bretschneider, R. J. Oudiz, Ph. Schnabel, J . Richter, H. Watanabe, R. Spahr, O. Obst, H. Mertens, A. Mülsch, R. Busse, D. Lamontagne, K. Herlan, A. Huang, E. Bassenae, J. R. L. Mackert, L. Schilling, A. A. Parsons, M. Wahl, M. Ph. Christmann, F. Thimm, M. Frey, a. A. Fleckenstein, H. Theilen, U. Göbel, W. Kuschinsky, Th. Elbert, M. Tafil-Klawe, H. Rau, W. Lutzenberger, A. Fleckenstein, H. Forst, M. Haller, C. Santjohanser, L. Lauterjung, Y. Smieško, D. J. Lang, P. C. Johnson, H. Schröck, T. Elbert, B Geiger, G. Koch, H. E. Koralewski, F. H. Perschel, K. Wagner, U. Krüger, M. Albrecht, G. Hohlbach, N. Maassen, M. Foerster, J. Mühling, F. Bari, K. Pleschka, H. D. Schmidt, H. Gro, W. Loock, C. Stick, U. Diefenbacher, D. Gronewold, M. Tobinsky, A. Walther-Behrends, E. Witzleb, M. Brummermann, R. E. Reinertsen, H. Rogausch, W. M. Rohn, H. Acker, M. Delpiano, E. Dufau, J. Hentschel, H. Heller, K. -D. Schuster, R. Siekmeier, H. Kronenberger, H. Lintl, Ch. F. Schiller-Scotland, J. Gebhart, J. Heyder, J. Meier-Sydow, W. Stahlhofen, K. Mottaghy, C. Geisen, W. Richter, J. Beckman, W. Marek, W. T. Ulmer, A. E. Thiele, F. Raschke, J. H. Peter, G. Hildebrandt, T. Kullmer, G. Kozianka-Burghof, M. E. Schlaefke, H. Gnuschke, T. Schaefer, D. Schaefer, C. Schaefer, Ronald J. Bradley, Raimund Sterz, Klaus Peper, R. Benterbusch, Th. Kraft, L. C. Yu, H. J. Kuhn, K. Blankenbach, G. Asmussen, I. Kunze, K. -S. Pieper, J. Steinmetz, H. Schmidt, P. Krippeit-Drews, U. Hübschen, A. C. Nacimiento, D. Günzel, W. Rathmayer, U. Gaunitz, D. Költgen, E. Zachar, B. Soltau, L. De Martino, W. Hasselbach, F. Kössler, P. Lange, G. Küchler, C. Zeugner, J. Van Eyk, R. S. Hodges, H. Lorkovic, N. Clemens, P. Scheid, Th. Noack, P. Deitmer, K. Golenhofen, E. Lammel, Andrea Welling, Jochen Felbel, Franz Hofmann, S. Katoch, T. Watanabe, K. Mandrek, K. Milenov, K. Hammer, W. Rössler, H. Sann, Fr -K. Pierau, H. Nguyen-Duong, P. Schneider, F. Stahl, A. Lepple-Wienhues, C. Korbmacher, H. Haller, M. Gebauer, U. Willner, C. Bialojan, M. Lengsfeld, V. Kyrtatas, Peter C. Dartsch, P. J. Boels, W. Fischer, T. Lenz, U. Thei, V. A. W. Kreye, T. Ohkubo, H. Kupp, M. Vonderlage, V. Schreiner, M. Dorlöchter, M. Brinkers, A. Irintchev, A. Wernig, B. Langenfeld, W. Finger, H. Wolburg, A. Beer, Ch. Schwejda, D. Scheller, U. Heister, F. Tegtmeier, Thomas Knöpfel, Andreas Spuler, Peter Grafe, Beat GÄhwiler, M. Bijak, U. Misgeld, W. Müller, G. Rausche, F M. Leweke, D. Bingmann, I. Moraidis, E. -J. Speckmann, M. Madeja, U. Mu\hoff, A Lehmenkühler, D. Kuhlmann, M. Hans, H. D. Lux, H. StrÄub, J. Waiden, R. E. Baker, R. Grantyn, M. Perouansky, K Kraszewski, Chr Lehmenkühler, H. U. Dodt, W. ZieglgÄnsberger, H. Pawelzik, W. ZieglgÄngsberger, K. Mann, H. Wiethölter, D. Albrecht, J. Dreier, E. Ficker, H. Beck, B J. Corrette, F. Dreyer, H. Repp, J. Dreessen, G. J. Augustine, A. Lehmenkühler, D. Büsselberg, B. Heimrich, H. L. Haas, S. Birnstiel, B. Schönrock, U. Altrup, H. Reith, C. Alzheimer, G. ten Bruagencate, B. Fruhstorfer, E. Mignot, S. Nishino, W. C. Dement, C. Guilleminault, Christa Simon-Oppermann, Olaf Günther, J. Stehle, S. Reuss, A. Seidel, R. Riemann, L. Vollrath, Susanne Reimer, Volker HölIt, U. Sonnhof, J. Krupp, H Claus, P. Hinckel, H. B. H. Dick, C. Hiemke, A. Jussofie, T. Dorn, S. Uhlig, O. W. Witte, B. Bother, M. Eiselt, H. Witte, ö Zwiener, M Rother, H. Eiseit, A. Taghavy, A. KrÄtzer, H. Clusmann, U. Heinemann, F. Block, K. -H. Sonatg, M. Falkeristein, J. Hohnsbein, J. Hoormann, A. Frieling, I. M. Tarkka, W. Kullmann, B. Bromm, M. Chr Hirsch, H. Wissing, H. A. Braun, P. Igelmund, F. W. Klu\mann, W. H. Ehrenstein, N. Yakimoff, S. Mateeff, M. L. Zeise, J. Arriagada, A. Teschemacher, T. Pöppelmann, R. Köhling, P. Boerrigter, K. Anders, W. Ohndorf, R. Dermietzel, D. W. Richter, T. R. Tölle, J. M. Castro-Lopes, Klinische Neuropharmakologie, J. Sandkühler, J. D. Leah, T. Herdegen, M. Zimmermann, D. Vaitl, H. Gnippe, M. K. Herbert, M. K. C. Mengel, K. -D. Kniffki, R. Linke, C. Vahle-Hinz, J. Schenda, K. Matsumura, Q. -G. fu, C. Forster, W. D. Hutchison, C. R. Morton, J. Aschoff, Z. Wilhelm, S. W. Schwarzacher, M Wasserschaff, M. Hörner, H. Kümmel, U. Windhorst, J. L. Feldman, K. Schmid, A. S. Foutz, M. Denavit-Saubié, M. A. Pak, P. Wehling, C. Evans, G. Bandara, F. Awiszus, H. Feistner, H. -J. Heinze, M. Illert, M. Wasserschaff, D. Kleinebeckel, G. Böhmer, W. Schauer, H. -H. Abel, D. Klü\endorf, H. P. Koepchen, W Jarolimek, St König, J. Czachurski, H. Seller, R. L. Meckler, E. M. McLachlan, A. Boczek-Funcke, H. -J. HÄbler, W. JÄnig, M. Michaelis, K. Dembowsky, S. Königr, Harald Rau, M. Unger, G. Merker, J. Roth, E. Zeisberger, H. Gao, M. Hunold, F. Kirchner, K. Takano, K. Schulze, M. Pokorski, Y. Sakakibara, A. Masuda, T. Morikawa, B. Ahn, S. Takaishi, P. -E. Paulev, Y. Honda, G. Flügge, E. Fuchs, S. König, U. Th. Eysel, R. Schmidt-Kastner, W. Skrandies, T. Geib, C. Baumann, K. -F. Schmidt, A. G. Knapp, J. E. Dowling, M. Kuba, N. Toyonaga, Z. Kubová, P. Jacobi, G. N. Nöll, Ch. Baumann, M. Tabata, Ch. Martin, H. Meissl, Th. Knottenberg, H. Scheibner, Hans P. Zenner, Ulrike Zimmennann, Alfred H. Gitter, D. Ding, J. W. T. Smolders, R. Klinke, I. Boekhoff, K. Raming, J. Krieger, E. Tareilus, J. Strotinann, H. Breer, D. Schild, J. A. DeSimone, S. Hellwig, A. H. Gitter, P. K. Plinkert, H. P. Zenner, M. Koltzenbwg, E. Pinter, K. SchÄfer, R. Necker, U. Hanesch, B. Heppelmann, R. F. Schmidt, S. Mense, U. Hoheisel, K. H. Steen, F. Anton, P. W. Reek, G. R. Lewin, S. B. McMahon, G. Heyer, O. P. Hornstein, W. Klement, J. O. Arndt, W. Maeerl, G. GrÄmer, K. Schepelmann, K. Me\linger, H. -G. Schaible, R. D. Treede, R. A. Meyer, J. N. Campbell, D. Claus, B. Neundörfer, R. Ernst, A. M. Tick-Waider, F. Bretschneider, R. C. Peters, P. F. M. Tennis, P. F. M. Teunis, D. Hoheisel, R. Scherotzke, A. Bub, G. Manzl, C. Jessen, B. Nuesslein, I. Schmidt, J. Wetzig, M. Reiser, N. Bregenzer, R. J. von Baumgarten, E. Mohr, H. Krzywanek, G. Warncke, K. -L. Schuchmann, H. Linow, F. H. Klu\mann, U. Redlin, G. Heldmaier, A Bamler, A. Koller, S. Felber, C. Haid, K. Wicke, E. Raas, Wang Xuemin, Chen Kerning, Shi Ying, Shi Hanping, Günther Warncke, R. Voisord, P. C. Dortsch, E. Betz, U. Karbach, S. Walenta, M. W. Gross, W. Mueller-Klieser, P. Vaupel, P. Okunieff, W. -K. Mayer, M. Stohrer, W. Krüger, W. Müller-Klieser, M. Strupp, P. Weial, H. Bostock, K. Piwernetz, R. Renner, P. Grafe, J. Lankers, W. Zangemeister, K. Kunze, S. Tries, H. Heinle, N. V. Beckerath, W. Maier-Rudolph, G. Mehrke, K. Günther, L. Goedel-Meinen, J. Daut, A. Kopp, T. Noll, A. Goellner, S. Gerlach, H. F. Teutsch, K. Schienger, R. Schwab, M. Höckel, Z. Fotev, M. Nienhaus, Gabriele Kaczmarczyk, Dinah Richter, Gabriele Korte, J. Förther, H. W. Reinhardt, R. Schreiber, J. Rupp, G. Murphy, J. Fingerle, O. Kloiber, T. Miyazawa, M. Höhn-Berlage, K. -A. Hossmann, H. Schad, W. Heimisch, R. Blasini, F. Haas, M. Mendier, A. Spuler, F. Lehmann-Hom, U. Wolfram, M. Fenske, N. Sachser, Ch. Weis, W. Marktl, B. Kopta, N. Klammer, B. Rudas, H. Pohl, A. Nienartowicz, W. Moll, M. Klempt, S. Blum, H. Bühler, I. Lichtenstein, A. Novak, H. Siebe, and K. Peper

Subjects
0303 health sciences, Physiology, Chemistry, Clinical Biochemistry, Tibialis Anterior, Human physiology, 030204 cardiovascular system & hematology, Pharmacology, Spring (mathematics), Article, Atrial Natriuretic Peptide, 03 medical and health sciences, 0302 clinical medicine, Atrial natriuretic peptide, Physiology (medical), Spreading Depression, Capsaicin, Extensor Digitorum Longus, 030304 developmental biology
Published
1990

19. Effects of miltefosine on various biochemical parameters in a panel of tumor cell lines with different sensitivities

Author

M, Rybczynska, M, Spitaler, N G, Knebel, G, Boeck, H, Grunicke, and J, Hofmann

Subjects
Cholesterol, Phosphorylcholine, Cell Cycle, Tumor Cells, Cultured, Humans, Antineoplastic Agents, Apoptosis, Biological Transport, Drug Screening Assays, Antitumor, Endocytosis, Phospholipids
Abstract

We investigated endocytosis activity, uptake of miltefosine (hexadecylphosphocholine), phospholipid and cholesterol content, the cell cycle, and apoptosis in 13 tumor cell lines (MCF7, MCF7/ADR, KB-3-1, KB-8-5, KB-C1, HeLa, HeLa-MDR1-G185, HeLa-MDR1-V185, CCRF/CEM, CCRF/VCR1000, CCRF/ADR5000, HL-60, HL-60/AR) with different sensitivities to treatment with the antitumor phospholipid analogues miltefosine and D-21266 (octadecyl-(N,N-dimethyl-piperidino-4-yl)-phosphate). In this panel of cell lines, MDR1 (multidrug resistance gene 1)- and MRP1 (multidrug resistance-associated protein)-expressing cells were found to be slightly more resistant to both compounds than sensitive parental cells. No correlation was found between resistance to miltefosine and endocytosis, intracellular concentration of miltefosine, the phospholipid and cholesterol content, induction of apoptosis, or cell cycle alterations in all the cell lines tested. Wild-type p53 containing WMN Burkitt's lymphoma cells and wild type p53-deficient CA46 exhibited similar sensitivities to miltefosine. The low percentage of apoptosis induced in MCF7 cells lacking caspase 3 indicated that caspase 3 seems to play an essential role in miltefosine-induced apoptosis.

Published
2001

20. Age-dependent deamidation of H1(0) histones in chromatin of mammalian tissues

Author

H, Lindner, B, Sarg, H, Grunicke, and W, Helliger

Subjects
Histones, Rats, Sprague-Dawley, Aging, Mice, Liver, Species Specificity, Animals, Brain, Kidney, Amides, Chromatin, Chromatography, High Pressure Liquid, Rats
Abstract

The composition of the H1(o) histone subfractions was examined in different rat and mouse tissues. Using reverse-phase HPLC and hydrophilic-interaction liquid chromatography we have found that the relative proportions of all four forms of H1(o) differ from tissue to tissue and from species to species. In principle, we observed an age-dependent increase in the amount of both the N-terminally acetylated (H1(o)a Asn-3 and H1(o)a Asp-3) and the deamidated forms of H1(o) (H1(o)a Asp-3 and H1(o)b Asp-3). Compared with the proportion of N-terminally acetylated H1(o) forms in liver, kidney and brain of rats and mice 20 days of age, we found an increase in these H1(o) subfractions of up to 30% in the corresponding organs of 300-day-old animals. The proportion of deamidated H1(o) forms was 1.6- to 4-fold higher in the livers and 8- to 12-fold higher in the brains of 300-day-old mice and rats, respectively, than in 20-day-old animals. The tissue-specific nature of the ratio of H1(o) subfractions suggests that the different forms of histone H1(o) have specific individual functions. The possible biological significance of age-related accumulation of N-terminal acetylated and deamidated histone H1(o) forms is discussed in the light of our results.

Published
1999

21. Epidermal growth factor (EGF) receptor blockade inhibits the action of EGF, insulin-like growth factor I, and a protein kinase A activator on the mitogen-activated protein kinase pathway in prostate cancer cell lines

Author

T, Putz, Z, Culig, I E, Eder, C, Nessler-Menardi, G, Bartsch, H, Grunicke, F, Uberall, and H, Klocker

Subjects
Enzyme Activation, ErbB Receptors, Male, Epidermal Growth Factor, Calcium-Calmodulin-Dependent Protein Kinases, Tumor Cells, Cultured, Humans, Prostatic Neoplasms, Insulin-Like Growth Factor I, Cyclic AMP-Dependent Protein Kinases, Signal Transduction
Abstract

Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are potent mitogens that regulate proliferation of prostate cancer cells via autocrine and paracrine loops and promote tumor metastasis. They exert their action through binding to the corresponding cell surface receptors that initiate an intracellular phosphorylation cascade, leading to the activation of mitogen-activated protein kinases (MAPKs), which recruit transcription factors. We have studied the effects of EGF, IGF-I, and the protein kinase A (PKA) activator forskolin on the activation of p42/ extracellular signal-regulated kinase (ERK)2, which is a key kinase in mediation of growth factor-induced mitogenesis in prostate cancer cells. The activity of p42/ERK2 was determined by immune complex kinase assays and by immunoblotting using a phospho p44/p42 MAPK-specific antibody. EGF, IGF-I, and forskolin-induced PKA activity stimulate intracellular signaling pathways converging at the level of p42/ERK2. In the androgen-insensitive DU145 cell line, there is a constitutive basal p42/ ERK2 activity that is not present in androgen-sensitive LNCaP cells. Constitutive p42/ERK2 activity is abrogated by blockade of the EGF receptor. Hence, it is obviously caused by an autocrine loop involving this receptor. The effects of EGF on p42/ERK2 are potentiated by forskolin in both cell lines. The blockade of PKA by the specific inhibitor H89 attenuates this synergism. This finding is in contrast to those obtained in several other systems studied thus far, in which PKA activators inhibited MAPKs. p42/ERK2 in DU145 cells is highly responsive to IGF-I stimulation, whereas no effect of IGF-I on p42/ERK2 can be measured in LNCaP cells. Moreover, our results demonstrate that selective blockade of the EGF receptor in prostate cancer cells does not only inhibit the action of EGF, but also IGF-I-induced activation of the MAPK pathway and the interaction with the PKA pathway. In conclusion, these findings offer new possibilities for a therapeutical intervention in prostate cancer by targeting signaling pathways of growth factors and PKA.

Published
1999

22. Conventional PKC-alpha, novel PKC-epsilon and PKC-theta, but not atypical PKC-lambda are MARCKS kinases in intact NIH 3T3 fibroblasts

Author

F, Uberall, S, Giselbrecht, K, Hellbert, F, Fresser, B, Bauer, M, Gschwendt, H H, Grunicke, and G, Baier

Subjects
Indoles, Molecular Sequence Data, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Proteins, 3T3 Cells, Isoenzymes, Maleimides, Mice, Enzyme Induction, Animals, Amino Acid Sequence, Enzyme Inhibitors, Phosphorylation, Myristoylated Alanine-Rich C Kinase Substrate, Phorbol 12,13-Dibutyrate, Protein Kinase C
Abstract

Phosphorylation of myristoylated alanine-rich protein kinase C substrate (MARCKS) in intact cells has been employed as an indicator for activation of protein kinase C (PKC). Specific PKC isoenzymes responsible for MARCKS phosphorylation under physiological conditions, however, remained to be identified. In our present study using stably transfected NIH 3T3 cell clones we demonstrate that expression of constitutively active mutants of either conventional cPKC-alpha or novel nPKC-epsilon increased phosphorylation of endogenous MARCKS in the absence of phorbol 12,13-dibutyrate in intact mouse fibroblasts, implicating that each of these PKC isoforms itself is sufficient to induce enhanced MARCKS phosphorylation. Similarly, ectopic expression of a constitutively active mutant of PKC-theta significantly increased MARCKS phosphorylation compared to vector controls, identifying PKC-theta as a MARCKS kinase. The PKC-specific inhibitor GF 109203X (bisindolylmaleimide I) reduced MARCKS phosphorylation in intact cells at a similar dose-response as enzymatic activity of recombinant isoenzymes cPKC-alpha, nPKC-epsilon, and nPKC-theta in vitro. Consistently, phorbol 12,13-dibutyrate-dependent MARCKS phosphorylation was significantly reduced in cell lines expressing dominant negative mutants of either PKC-alpha K368R or (dominant negative) PKC-epsilon K436R. The fact, that the constitutively active PKC-lambda A119E mutant did not alter the MARCKS phosphorylation underscores the assumption that atypical PKC isoforms are not involved in this process. We conclude that under physiological conditions, conventional cPKC-alpha and novel nPKC-epsilon, but not atypical aPKC-lambda are responsible for MARCKS phosphorylation in intact NIH 3T3 fibroblasts.

Published
1997

23. Interference of new alkylphospholipid analogues with mitogenic signal transduction

Author

K, Maly, F, Uberall, C, Schubert, E, Kindler, J, Stekar, H, Brachwitz, and H H, Grunicke

Subjects
Sodium-Hydrogen Exchangers, Cell-Free System, Genes, fos, Antineoplastic Agents, 3T3 Cells, Inositol 1,4,5-Trisphosphate, Mice, Gene Expression Regulation, Type C Phospholipases, Animals, Tetradecanoylphorbol Acetate, Calcium, Receptors, Thrombin, Promoter Regions, Genetic, Cell Division, Phospholipids, Protein Kinase C, Signal Transduction
Abstract

The interference of several new hexadecylphosphocholine analogues with mitogenic signal transduction was investigated in NIH3T3 fibroblasts by studying the effects of these agents on thrombin-induced inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) formation and the subsequent Ca2+ release, on protein kinase C (PKC) in cell-free extracts, on the PKC-mediated activation of the Na+/H+ antiporter and on c-fos induction. The compounds investigated include hexadecylphosphocholine (HePC), octadecyl-[2-(N-methyl-piperidinio)-ethyl]-phosphate (D20133), octadecyl-(N,N-dimethyl-piperidinio-4-yl)-phosphate (D21266); octadecyl-[2-(trimethyl-arsonio)-ethyl]-phosphate (D21805) and hexadecylphospho-L-serine (HePS). The data indicate that (i) all compounds inhibit the thrombin-induced progression of growth-arrested NIH3T3 cells into S phase with similar IC50 values; (ii) the common denominator of all compounds is a reduction of Ins(1,4,5)P3 formation, resulting in an attenuation of Ca2+ release; (iii) the direct interaction with PKC does not significantly contribute to the antitumor activity of these agents; (iv) the new HePC congeners D21266, D21133 and D21805 affect the same targets as HePC, i.e. PKC and phosphatidylinositol 4,5-bisphosphate-specific phospholipase C (PLC). The lower toxicities of these compounds cannot be explained by a less pronounced inhibition of PKC or PLC, respectively.

Published
1995

24. Signal transduction inhibitors

Author

H. Grunicke

Subjects
Cancer Research, Text mining, Oncology, business.industry, Neoplasms, Medicine, Humans, Computational biology, Signal transduction, Enzyme Inhibitors, business, Signal Transduction
Published
1995

25. Reviews of Physiology, Biochemistry and Pharmacology 151

Author

Susan G Amara, Ernst Bamberg, H. Grunicke, Reinhard Jahn, W.J. Lederer, Atsushi Miyajima, H. Murer, Stefan Offermanns, G. Schultz, M. Schweiger, Susan G Amara, Ernst Bamberg, H. Grunicke, Reinhard Jahn, W.J. Lederer, Atsushi Miyajima, H. Murer, Stefan Offermanns, G. Schultz, and M. Schweiger

Subjects
Medicine—Research, Biology—Research
Abstract

H. Wegele, L. Müller, and J. Buchner: Hsp70 and Hsp90 – A Relay Team for Protein Folding R. Schülein: The Early Stages of the Intracellular Transport of Membrane Proteins: Clinical and Pharmacological Implications L. Schild: The Epithelial Sodium Channel: From Molecule to Disease

Published
2007

26. Reviews of Physiology, Biochemistry and Pharmacology 149

Author

S. G. Amara, E. Bamberg, M. P. Blaustein, H. Grunicke, R. Jahn, W. J. Lederer, A. Miyajima, H. Murer, S. Offermanns, N. Pfanner, G. Schultz, M. Schweiger, S. G. Amara, E. Bamberg, M. P. Blaustein, H. Grunicke, R. Jahn, W. J. Lederer, A. Miyajima, H. Murer, S. Offermanns, N. Pfanner, G. Schultz, and M. Schweiger

Subjects
Cytokines, Proteins, Clinical biochemistry
Abstract

D. Kamimura, K. Ishihara, T. Hirano: IL-6 Signal Transduction and its Physiological Roles: The Signal Orchestration Model M. Tanaka and A. Miyajima: Oncostatin M, a Multifunctional Cytokine G.-J. van de Geijn, L.H.J. Aarts, S.J. Erkeland, J. Prasher, and I.P. Touw: Granulocyte Colony-Stimulating Factor and its Receptor in Normal Hematopoietic Cell Development and Myeloid Disease T. Hanada, I. Kinjyo, K. Inagaki-Ohara and A. Yoshimura: Negative Regulation of Cytokine Signaling by CES/SOCS Family Proteins and Their Roles in Inflammatory Diseases J. Kalesnikoff, L.M. Sly, M.R. Hughes, T. Büchse, M.J. Rauh, L.-P. Cao, V. Lam, A. Mui, M. Huber, and G. Krystal: The Role of SHIP in Cytokine-Induced Signaling

Published
2007

27. Reviews of Physiology, Biochemistry and Pharmacology, Volume 124

Author

M. Schweiger, M. P. Blaustein, E. Habermann, D. Pette, H. Reuter, E. M. Wright, H. Grunicke, B. Sakmann, and E. R. Weibel

Subjects
Engineering, business.industry, Physiology, Computational biology, business, Volume (compression)
Published
1994

28. Role of protein kinases in antitumor drug resistance

Author

Johann Hofmann, H. Grunicke, Florian Überall, and I. Utz

Subjects
MAP kinase kinase kinase, Cyclin-dependent kinase 2, Drug Resistance, Antineoplastic Agents, Hematology, General Medicine, Biology, Mitogen-activated protein kinase kinase, Cell biology, MAP2K7, Mice, DNA Topoisomerases, Type II, Genes, ras, Biochemistry, biology.protein, Tumor Cells, Cultured, Animals, ASK1, c-Raf, Carcinoma 256, Walker, Cisplatin, Protein kinase A, Protein Kinase Inhibitors, Protein Kinases, Protein kinase C
Abstract

The activity of several proteins involved in the development of antitumor drug resistance is regulated by protein phosphorylation. These proteins include the mdr-1-encoded P-glycoprotein (Pgp) and topoisomerase II (topo II). The corresponding evidence is reviewed and attempts to modulate multidrug resistance (MDR) by protein kinase C inhibitors are described. The expression of several proteins which are essential in drug resistance is regulated at the transcriptional level, involving protein phosphorylation by members of the protein kinase C (PKC) family, casein kinase II (CKII), and others. These proteins include mdr-1-encoded P-glycoprotein, metallothionein, glutathione S-transferase (GST), dTMP synthase, and the proteins Fos and Jun. The corresponding genes are under positive regulation of ras, which in turn requires the activation of a protein kinase cascade for its function. Protein kinases are therefore potentially useful targets in reducing the expression of proteins involved in the development of multifactorial drug resistance caused by the expression of transforming ras-genes. Attempts to inhibit the ras-induced fos expression by an inhibitor of protein kinase C (ilmofosine) are described. Protein kinase inhibitors are also able to synergistically enhance the cytotoxicity of cis-platinum, which is discussed as resulting from a reduction of PKC-dependent fos expression.

Published
1994

29. Role of GTPases and GTPase regulatory proteins in oncogenesis

Author

H H, Grunicke and K, Maly

Subjects
GTP-Binding Proteins, Neoplasms, Animals, Humans, Genes, Tumor Suppressor, Oncogenes, GTP Phosphohydrolases
Abstract

The GTPases comprise a superfamily of GTP-binding proteins with intrinsic GTPase activity. Some members of this family representing either heterotrimeric or small G-proteins are involved in the transmission of mitogenic signals. Mutations that lead to constitutively activated G-proteins have been shown to contribute to malignant transformation. These genes represent, therefore, putative oncogenes. Examples are the gsp and gip2 oncogenes, encoding GTPase deficient alpha-subnits of Gs or Gi-2 proteins. Representatives from the family of small G-proteins are the products of the Harvey-, Kirsten- or N-ras oncogenes. These oncogenes, which are frequently expressed in human malignancies, code for proteins (p21ras) that are locked in the activated GTP-bound state because their GTPase is refractory to the ras-specific GTPase activating protein (GAP). In other cases p21ras-GTP levels have been found to be elevated as a result of an increase in GDP/GTP exchange rate. In neurofibromatosis v. Recklinghausen, a mutated gene (NF1) is detectable. The protein encoded by NF1 contains a GAP homology region, binds p21ras-GTP, and stimulates the hydrolysis of p21ras-bound GTP. Both ras-GAP (p120 GAP) and NF1-GAP are inhibited by acidic lipids. Elevated levels of these lipids may exert growth-stimulatory or perhaps tumor-promoting activity by increasing p21ras GTP. The function of transforming p21ras is under control of tumor suppressor genes. Putative suppressor genes isolated from revertants from ras-transformed cells include rsp-1 and the ras recision gene (rrg). Experimentally, an overexpression of Rap 1A/Krev-1 is able to antagonize transformation by p21ras. This mechanism also may be relevant under normal conditions. p53 also is capable of inhibiting transforming p21ras. It is postulated that p105-RB exerts a similar anti-ras effect. The mechanism by which retinoic acid suppresses transformation by ras is discussed. Current strategies for a pharmacological interference of p21ras function are described.

Published
1993

30. Protein kinase C modulation

Author

H H, Grunicke and F, Uberall

Subjects
Humans, Antineoplastic Agents, Protein Kinase C
Abstract

PKC-modulators represent valuable additions to the arsenal of anti-tumor agents. They act as antiproliferative agents and are useful in overcoming drug-resistance by inhibiting mdr-mediated drug efflux. They increase the cytotoxicity to platinum complexes (and other DNA-damaging agents), probably by interfering with drug-induced detoxification and repair mechanisms. PKC-modulators are potentially active in overcoming ras-induced cis-platinum-resistance by antagonizing p21ras functions.

Published
1992

31. Hexadecylphosphocholine inhibits inositol phosphate formation and protein kinase C activity

Author

F, Uberall, H, Oberhuber, K, Maly, J, Zaknun, L, Demuth, and H H, Grunicke

Subjects
Sodium-Hydrogen Exchangers, Inositol Phosphates, Phosphorylcholine, Tumor Cells, Cultured, Tetradecanoylphorbol Acetate, Bombesin, Lithium, Carrier Proteins, Cell Division, Protein Kinase C
Abstract

Hexadecylphosphocholine (HePC) inhibits protein kinase C (PKC) from NIH3T3 cells in cell-free extracts with a 50% inhibitory concentration of about 7 microM. Inhibition is competitive with regard to phosphatidylserine with a Ki of 0.59 microM. In order to determine whether HePC affects PKC in intact cells, the bombesin or tetradecanoylphorbolacetate-induced, PKC-mediated activation of the Na+/H(+)-antiporter was determined. It is demonstrated that HePC causes a drastic inhibition of this enzyme indicating a similar sensitivity of PKC to HePC in intact cells compared to cell-free extracts. In addition to the effects on PKC, treatment of NIH3T3 cells with HePC depresses the bombesin-induced formation of inositol 1,4,5-trisphosphate and the concomitant mobilization of intracellular Ca2+. Dose-response curves for the inhibition of inositol 1,4,5-trisphosphate formation and Ca2+ mobilization reveal 50% inhibitory concentrations of 2 or 5 microM, respectively. Polyphosphorylated phosphoinositides accumulate in HePC-treated cells indicating that the depression of inositol 1,4,5-trisphosphate generation is not caused by an inhibition of phosphoinositide kinases. Addition of bombesin to HePC-treated cells in the presence of LiCl revealed no evidence for an accelerated rate of inositol 1,4,5-trisphosphate turnover by the phospholipid analogue. It is concluded that HePC inhibits phosphoinositidase C in intact cells. The data strongly suggest that the growth-inhibitory effect of HePC is at least in part explained by the interference with mitogenic signal transduction.

Published
1991

32. Mechanism of desensitization of the Ca2(+)-mobilizing system to bombesin by Ha-ras. Independence from down-modulation of agonist-stimulated inositol phosphate production

Author

H, Oberhuber, K, Maly, F, Uberall, J, Hoflacher, A, Kiani, and H H, Grunicke

Subjects
Gene Expression, Inositol 1,4,5-Trisphosphate, Oncogene Protein p21(ras), Phosphatidylinositols, Cell Compartmentation, Cell Line, Mitochondria, Proto-Oncogene Proteins p21(ras), Mice, Genes, ras, Proto-Oncogenes, Animals, Bombesin, Calcium, Calcium Channels, Calcimycin, Signal Transduction
Abstract

Expression of a transforming Ha-ras gene in NIH 3T3 cells transfected with an inducible Ha-ras construct leads to a rapid desensitization of the intracellular Ca2(+)-mobilizing system to bombesin and serum growth factors. Half-maximal depression of the Ca2+ response is observed 2 h after induction of p21ras. A maximum is obtained after 6 h. Bombesin-induced elevation of inositol 1,4,5-trisphosphate formation is also depressed in cells expressing Ha-ras. This, however, is a relatively late phenomenon and not yet detectable when maximal depression of the Ca2+ signal is observed. We conclude that the rapid densensitization of the Ca2(+)-releasing system to bombesin by Ha-ras is not caused by down-modulation or uncoupling of phospholipase C-coupled bombesin receptors. The inositol 1,4,5-trisphosphate-mediated release of intracellular Ca2+ is reduced in permeabilized cells expressing the Ha-ras oncogene. A depletion of intracellular Ca2+ stores by Ha-ras is unlikely since (i) the Ha-ras-induced growth factor-independent stimulation of inositol phosphate formation occurs several hours after reduction of the Ca2+ response and (ii) the Ca2+ load of intracellular nonmitochondrial Ca2+ stores was found to be unaffected by Ha-ras. We conclude that the desensitization of the Ca2(+)-mobilizing system is caused either by partial inhibition of inositol 1,4,5-trisphosphate-regulated Ca2+ channels or by interference of Ha-ras with Ca2+ translocation between intracellular Ca2+ compartments.

Published
1991

33. Reviews of Physiology, Biochemistry and Pharmacology, Volume 118

Author

H. Grunicke, E. M. Wright, D. Pette, E. Habermann, H. Reuter, M. P. Blaustein, O. Creutzfeldt, M. Schweiger, S. Numa, and B. Sakmann

Subjects
Engineering, business.industry, Physiology, Computational biology, business, Volume (compression)
Published
1991

34. Reviews of Physiology, Biochemistry and Pharmacology

Author

M. P. Blaustein, H. Grunicke, E. Habermann, D. Pette, H. Reuter, B. Sakmann, M. Schweiger, E. M. Wright, M. P. Blaustein, H. Grunicke, E. Habermann, D. Pette, H. Reuter, B. Sakmann, M. Schweiger, and E. M. Wright

Subjects
Pharmacology, Biochemistry, Cytology
Published
2006

43. Absract

Author

Marietta Kaszkin, Volker Kinzel, Karl Maly, Irina Bichler, Florian Lang, Hans H. Grunicke, R. Pepperkok, R. Jakobi, P. Lorenz, W. Ansorge, W. Pyerin, P. Borowski, M. Harbers, A. Ludwig, T. Kischel, H. Hilz, K. Eckert, A. Granetzny, J. Fischer, R. Grosse, V. Manch, S. Wehner, B. Kornhuber, U. Ebener, K. Müller-Decker, G. Fürstenberger, I. Vogt, F. Marks, G. Graschew, A. Küsel, W. Hull, W. Lorenz, H. W. Thielmann, Gisela H. Degen, Alexius Freyberger, A. Müller, M. Linscheid, Ulrike Hindermeier, Ute Jorritsma, K. Golka, W. Föllmann, H. Peter, H. M. Bolt, S. Monnerjahn, D. N. Phillips, A. Never, A. Seidel, A. R. Glatt, K. Wiench, E. Frei, P. Schroth, M. Wiessler, T. Schäfer, M. Hergenhahn, E. Hecker, D. Proft, P. Bartholmes, R. S. Bagewadikar, B. Bertram, N. Frank, Hanno Leibersperger, Michael Gschwendt, Friedrich Marks, S. Fasco, Peter Plein, Karin Schiess, Lothar Seidler, T. Jacobi, E. Besemfelder, M. Stephan, W. D. Lehmann, M. Grell, B. Thoma, P. Scheurich, Markus Meyer, Hans Grunicke, G. Jaques, B. Wegmann, K. Ravemann, Odilia Popanda, Heinz Walter Thielmann, H. Voss, U. Wirkner, Dieter Werner, D. Strand, A. Kalmes, H. -P. Walther, B. Mechler, S. Volker Schirrmacher, V. Kinzel, R. Hess, H. -G. Hanagarth, C. Hässler, G. Brandner, Christian Ertel, B. Gückel, V. Schirrmacher, B. A. Kyewski, U. Bogdahn, P. Jachimczak, J. Schneider, W. Brysch, W. Schlingensiepen, D. Drenkard, C. Behl, J. Winkler, R. Apfel, J. Meixensberger, K. Stulle, P. Marquardt, H. P. Vollmers, J. Müller, H. -K. Müller-Hermelink, M. Schuermann, G. Seemann, Angelika Ptok, M. Ptok, T. E. Carey, M. Steffen, U. C. Nitz, B. Everding, F. Hölzel, G. Kantwerk-Funke, G. Boll, K. S. Zänker, P. Hölzel, J. Heymanns, C. Hennig, M. Rotsch, K. Havemann, Jürgen R. Fischer, Sabine Stehr, Harald Lahm, Peter Drings, Peter H. Krammer, M. Kirsch, A. Strubel, A. Kist, R. Hinn, H. Fischer, A. Buttler, G. Schackert, S. Friedenauer, D. Lindner, B. Marczynski, H. Karcls, H. W. Goergens, B. Epe, E. Müller, D. Schütze, S. Boiteux, E. Eder, C. Deininger, C. Hoffman, E. Scherer, E. Vermeulen, H. J. van Kranen, J. Bax, R. A. Woutersen, C. F. van Kreijl, B. Schurich, H. Hagedorn, E. Kamp, G. Eisenbrand, B. Spiegelhalder, U. Bolm-Audorff, H. G. Bienfait, R. Preussmann, C. -D. Wacker, H. Kehl, Z. Akkan, J. Ries, M. Meger, S. E. Shephard, D. Gunz, W. K. Lutz, A. R. Tricker, R. Kurnar, M. Siddiqi, P. Mende, B. Pfundstein, A. Scholl, C. Janzowski, D. Jacob, P. Goelzer, I. Henn, H. Zankl, K. -H. Zimlich, Barbara Gansewendt, Ricarda Thier, K. R. Schroeder, E. Hallier, G. Moeckel, W. Heiden, M. Waldherr-Teschner, J. Brickmann, H. Roeser, G. Krauter, G. Scherer, A. Krätschmer, H. Hauenstein, F. Adlkofer, R. C. Fernando, H. H. Schmeiser, W. Nicklas, Wolfgang Pfau, David H. Phillips, S. Scheckenbach, S. Cantoreggi, Monika Leutbecher, H. Ottenwälder, U. Föst, P. M. Baumgart, H. -C. Kliem, S. Data, C. Pfeiffer, A. Fuchs, P. Schmezer, F. Kuchenmeister, B. L. Pool-Zober, U. M. Liegibel, B. L. Pool-Zobel, L. Steeb, H. Friesel, Th. Schneider, H. R. Scherf, A. Buchmann, R. Bauer-Hofmann, J. Mahr, M. Schwarz, R. Schmidt, F. Rippmann, B. Steinbauer, P. Zlfu, B. Bunk, W. Hefter, K. Klinga, M. R. Berger, L. W. Robertson, G. Luebeck, S. Moolgavkar, U. Torsten, M. Kowalczyk-Wagner, H. Weitzel, Ch. Zechel, H. Peters, F. Anders, S. Ambs, T. Kirchner, H. -G. Neumann, C. Einig, E. Eigenbrodt, D. Oesterle, E. Deml, G. Weisse, U. Gerbracht, H. Stumpf, E. Filsingcr, P. Bannasch, W. Muster, P. Cikryt, P. Münzel, E. Röhrdanz, K. W. Bock, H. -P. Lipp, T. Wiesmüller, H. Hagenmaier, D. Schrenk, A. Karger, G. Bauer, P. Höfler, M. Götschl, E. Viesel, J. Jürgensmeier, D. Schaefer, G. Picht, J. Kiefer, P. Krieg, R. Schnapke, S. Feil, E. Wagner, U. Schleenbecker, A. Anders, M. M. Gross, S. Unger, E. J. Stanbridge, Petra Boukamp, Ulrich Pascheberg, Norbert E. Fusenig, H. Abken, U. H. Weidle, F. Grummt, K. Willecke, R. Schäfer, A. Hajnal, I. Balmer, R. Klemenz, P. E. Goretzki, H. Reishaus, M. Demeure, H. Haubruck, J. Lyons, H. D. Röher, Sylvia Trouliaris, Angelika Hadwiger-Fangmeier, Elke Simon, Heiner Niemann, Teruko Tamura, G. Westphal, Elke Turner, H. Karels, M. Blaszkewicz, Helga Stopper, Dietmar Schiffmann, Umberto De Boni, M. Schuler, R. Schnitzler, M. Metzler, E. Pfeiffer, R. Aulenbacher, T. Langhof, K. R. Schröder, K. Saal, H. K. Müller-Hermelink, W. Henn, G. Seitz, P. Lagoda, A. Christmann, N. Blin, C. Welter, D. Adam, D. Fömzler, C. Winkler, W. Mäueler, M. Schartl, B. Theisinger, G. Schüder, U. Rüther, C. Nunnensiek, H. A. G. Müller, W. Rupp, M. Lüthgens, P. Jipp, I. Kinzler, M. Gulich, H. J. Seidel, O. H. Clark, F. McCormick, H. R. Bourne, F. Gieseler, F. Boege, H. Biersack, B. Spohn, M. Clark, K. Wilms, Fritz Boege, Frank Gieseler, Harald Biersack, Michael Clark, Klaus Wllms, Axel Polack, Lothar Strobl, Regina Feederle, Matthias Schweizer, Dirk Eick, Georg W. Bornkamm, M. Kopun, H. Scherthan, C. Granzow, P. Janiaud, D. Rueß, B. M. Mechler, P. G. Strauss, V. Erfle, M. Fritsche, C. Haessler, H. Christiansen, J. Schestag, N. M. Christiansen, F. Lampert, Wolfgang A. Schulz, Andreas Hasse, Helmut Sies, G. Orend, I. Kuhlmann, W. Doerfler, A. Behn-Krappa, I. Hölker, U. Sandaradura de Silva, Ute Smola, Dagmar Hennig, Angelika Hadviger-Fangmeier, Burkhard Schütz, R. Kerler, H. M. Rabes, G. Dölken, A. A. Fauser, R. Kerkert, U. Ragoczy, R. Fritzen, W. Lange, J. Finke, B. Nowicki, E. Schalipp, W. Siegert, R. Mertelsmann, U. Schilling, H. J. Sinn, W. Maier-Borst, E. A. Friedrich, E. Löhde, M. Lück, H. Raude, H. Schlicker, G. Barzen, E. Kraas, J. Milleck, R. Keymer, S. Störkel, T. Reichert, F. Steinbach, R. Lippold, W. Thoenes, W. Wagner, K. -A. Reiffen, A. Bardosi, D. Brkovic, H. -J. Gabius, B. Brandt, C. Jackisch, D. Seitzer, M. Hillebrand, F. A. Habermann, null Zeindl-Eberhart, null Evelyn, C. Robl, V. Röttgen, C. Nowak, H. -B. Richter-Reichhelm, V. Waldmann, B. Suchy, Ch. Zietz, M. Sarafoff, Richard Ostermayr, Hartmut M. Rabes, J. Lorenz, T. Friedberg, W. Paulus, R. Ferlinz, F. Oesch, E. Jähde, K. -H. Glüsenkamp, L. F. Tietze, M. F. Rajewsky, G. Chen, K. -J. Hutter, J. Bullerdiek, W. J. Zeller, M. Schirner, M. R. Schneider, P. Zbu, M. Gebelein, B. Naser-Hijazi, Nancy E. Hynes, M. Reinhardt, P. Heyl, D. Schmähl, P. Presek, U. Liebenhoff, D. Findik, G. H. Hartmann, C. Kliesch, F. Albert, S. Kunze, M. Wannnenmacher, J. Boese-Landgraf, E. Lorenz, D. Albrecht, M. Dulce, K. R. Aigner, N. Thiem, H. Müller, M. Leonardi, A. Justh, M. Lutz, E. Lang, C. W. v. d. Lieth, H. Sinn, B. R. Betsch, Jan Georg Hengstler, Jürgen Fuchs, Franz Oesch, F. J. Busch, A. B. C. Cato, G. Schied, W. Tang, B. Richter, C. Schaefer, D. K. Kelleher, P. Vaupel, D. Mundt, H. H. Bartsch, H. Meden, M. Meyer, K. Vehmeyer, R. Mull, W. Kuhn, S. Hoffmann, D. Berger, H. Fiebig, Ch. Moog, B. Luu, S. Frühauf, B. K. Keppler, A. Galeano, P. Valenzuela-Paz, T. Klenner, H. Stadler, G. Golomb, E. Breuer, R. Voegeli, P. Hilgard, H. R. Nowrousian, P. Aulenbacher, B. Winterhalter, C. Granson, M. Stöhr, H. Ponstingl, P. Drings, H. Osswald, S. B. Sobottka, E. Amtmann, G. Sauer, B. Hornung, S. Volland, S. Kahl, R. Gerspach, B. Matz, J. Schmidt, M. Lipp, G. Brehm, A. Luz, S. Wendel, P. G. Strauß, V. Erflte, S. Greehmann, A. Zobel, F. Kalkbrenner, G. Vorbrüggen, K. Moelling, T. Iftner, A. H. Müller, P. G. Fuchs, H. Pfister, Klaus Cichutek, Iris Treinies, Matthias Lang, C. Braun, J. Denner, S. Norley, R. Kurth, L. Music, O. D. Wiestler, A. Aguzzi, A. von Deimling, M. Schneemann, R. Elbl, P. Kleihues, H. Land, H. -P. Hohn, M. Höök, H. -W. Denker, W. Kemmner, K. Zaar, Peter A. Jones, R. Kath, M. Herlyn, P. Maier, H. P. Schawalder, J. Elsner, W. Parzefall, E. Erber, R. Sedivy, R. Schulte-Hermann, J. Hemmer, P. Tomakidi, P. Boukamp, D. Breitkreutz, N. E. Fusenig, F. Kallinowski, W. Strauss, A. L. Brownell, I. D. Bassukas, G. Vester, B. Maurer-Schultze, L. Langbein, H. Kosmehl, D. Katenkamp, Eberhard Spiess, Günther Trefz, Werner Ebert, Peter Jordan, Dieter Kübler, Rosemarie B. Lichtner, Marion Wiedemuth, Annette Kittmann, Axel Ullrich, Khashayarsha Khazaie, Aiga Kowitz, Guni Kadmon, Peter Altevogt, U. H. Frixen, J. Behrens, J. Schipper, M. Sachs, H. Birchmeier, R. Hackenberg, Th. Hawighorst, J. Hofmann, H. Beato, K. -D. Schulz, C. Erbil, M. Maasberg, L. A. Kunz, A. Simm, G. Adam, W. Mueller-Klieser, Andreas M. Kaufmann, Michael Stoeck, A. Hülsen, S. Game, M. Donnelly, H. -J. Stark, K. -H. Schlingensiepen, U. Kurzik-Dumke, B. Phannavong, D. Gundacker, E. Gateff, S. Gabius, S. S. Joshi, H. Franz, N. J. John, R. Grümmer, H. W. Denker, M. W. Gross, and U. Karbach

Subjects
Cancer Research, Oncology, General Medicine
Published
1991

44. Depression of histone acetylation by alkylating antitumor agents: significance for antitumor activity and possible biological consequences

Author

Wilfried Helliger, Bernd Puschendorf, S. Hauptlorenz, Adam Csordas, I. Multhaup, H. Zwierzina, A. Loidl, and H. Grunicke

Subjects
Cancer Research, Alkylation, Transcription, Genetic, In Vitro Techniques, Biology, Histones, Mice, Genetics, Animals, Mechlorethamine, Carcinoma, Ehrlich Tumor, Cyclophosphamide, Molecular Biology, Phospholipids, Histone deacetylase 5, HDAC11, Histone deacetylase 2, HDAC8, Chromatin, Rats, Butyrates, Histone, Acetylation, Histone methyltransferase, Cancer research, biology.protein, Butyric Acid, Molecular Medicine, Electrophoresis, Polyacrylamide Gel, Puromycin, Triaziquone, Histone deacetylase
Abstract

Treatment of Ehrlich ascites tumor cells with the alkylating antitumor agents triaziquonum, N-mustard and cyclophosphamide leads to a reduction in the posttranslational incorporation of 3H-acetate into histones and the extent of histone acetylation in Ehrlich ascites tumor cells. All core histones are affected. The depression of histone acetylation is not the result of a decrease in acetyl-CoA. Evidence is presented for an activation of histone deacetylase by alkylating agents. A reduction of histone deacetylation is observed after exposure to all concentrations of alkylating agents which inhibit cell proliferation. In order to evaluate the biological consequences of a reduction of histone acetylation, the extent of acetylation was modulated by either chemical acetylation or treatment with butyrate. In all cases an increase in histone acetylation leads to an enhancement of the rate of transcription. In accord with previous reports from our laboratory (1), it is concluded that the reduction of histone acetylation affects RNA synthesis. It is emphasized, however, that besides a regulation of transcription, histone acetylation may be involved in other cell functions. Thus, the complete biological consequences of the reduction of histone acetylation remain to be elucidated. In view of the antitumor activity of the alkylating agents it seems noteworthy that hepatoma AS30D cells are characterized by a remarkably higher extent of histone H4-acetylation compared to normal, adult, fetal, or regenerating liver.

Published
1984

45. Some data on the basic metabolism of trout eggs

Author

R. Peter, H. Grunicke, G. Czihak, and B. Puschendorf

Subjects
biology, urogenital system, Ecology, Zoology, Metabolism, Aquatic Science, biology.organism_classification, Trout, Human fertilization, Blood serum, embryonic structures, Coelom, Electrolyte composition, Ecology, Evolution, Behavior and Systematics
Abstract

Oxygen consumption was found to be essentially the same in unfertilized trout eggs, water activated eggs and eggs immediately after fertilization. Trout eggs are capable of regulating the pH of the surrounding medium probably by releasing buffering electrolytes. The electrolyte composition of the coelomic fluid is close to normal vertebrate blood serum. The coelomic fluid may permit further growth of ovulated eggs before spawning.

Published
1979

46. Plasma membrane as target of alkylating agents

Author

Wolfgang Doppler, J.J. Roberts, K. Maly, H. Oberhuber, Herbert Lindner, H. Ringsdorf, H. Grunicke, and Johann Hofmann

Subjects
Alkylating Agents, Cancer Research, Calmodulin, Antiporter, Cell, Phospholipase, Cell Line, chemistry.chemical_compound, Genetics, medicine, Animals, Mechlorethamine, Carcinoma 256, Walker, Carcinoma, Ehrlich Tumor, Molecular Biology, Cells, Cultured, Adenosine Triphosphatases, chemistry.chemical_classification, biology, Chlorambucil, Chemistry, Cell Membrane, DNA, Calcium Channel Blockers, medicine.anatomical_structure, Enzyme, Biochemistry, Quinacrine, Potassium, biology.protein, Molecular Medicine, Cotransporter, Cell Division, medicine.drug
Abstract

N mustard resistant Walker cells exhibit the same frequency of DNA interstrand cross-links and the same rate of cross-link removal as the sensitive parental line. Employing cytostatically active concentrations of chlorambucil covalently bound to polyethyleneimine, the extent of DNA cross-linking is reduced to levels observed in the presence of nontoxic concentrations of free chlorambucil. It is concluded, therefore, that DNA cross-links alone are not sufficient to explain the inhibition of cell multiplication by alkylating agents and that additional mechanisms have to be considered. Evidence for an interference of alkylating agents with several enzymes of the plasma membrane is presented. An inhibition by N mustard of the furosemide-sensitive Na + /K + /Cl − -cotransport and the Na + /H + -antiport is described in greater detail. Considering the fact that the enzymes which are affected by alkylating agents are controlled by growth factors it was investigated whether a synergism between inhibitors of early growth-factor-controlled reactions and alkylating agents is to be seen. It is demonstrated that mepacrine, an inhibitor of phospholipase C, and the calmodulin binding drugs, chloropromazine and flunarizine, amplify the action of N mustard.

Published
1985

47. Contents, Vol. 24, Supplement 2, 1984

Author

M. Pickel, L. Schausberger, J. Huber, H. Hofmann, A. Stary, E. Reinold, G. Breitenecker, P. Sevelda, H. Grunicke, Ch. Schieder, P. Anderl, M.O. Schweditsch, F. Nagl, W. Müller-Hartburg, W.D. Skodler, A.W. Kowatsch, J.C. Huber, S. Leodolter, J.H. Holzner, N.S. Assali, M. Lahousen, J. Hosmann, M. Langer, B. Bartosch, W. Bartl, H.-H. Arns, F. Floder, N. Wasserstrum, C. Hellmich, G. Simbruner, A. Hetzenauer, M. Neumann, Elisabeth Karpellus, H. Kölbl, Ch. Bali, R. Schmid, R. Rudelstorfer, F. Kainer, I. Rost, R. Wiborny, B. Stadler, W. Loos, J. Söltz-Szöts, F. Friedrich, E. Golob, H. Salzer, K. Swolin, J. Spona, Ch. Löffler, G. Fodor, Zeichen Hl, G. Fuchs, S. Szalay, A. Euller, J. Lahodny, F. Fischl, O. Sedlak, Margit Endler, L. Wiebogen, G. Daxenbichler, Ch. Dalbauer, G. Tscherne, A. Jorde, N. Pateisky, A. Bichler, A. Beck, R. Hawliczek, M.M. Metka, H.G.K. Mayer, P.W. Klug, M. Nachtigall, G. Wolf, W. Moser, Ch. Vutuc, Maria Hengstberger, A. Kowatsch, B. Hamann, K. Tabsh, H.O. Mayer, E. Holzer, H.J. Nesser, K. Schieder, D. Skodler, K. Irsigler, O. Dapunt, E. Gitsch, A. Khoury, K. Rosanelli, H. Huber, K. Baumgarten, H. Hirschmann, Ch. Pfersmann, H. Graeff, Brigitte Schurz, D. Zwierzina, P.A.M. Weiß, W. Knogler, N. Zeibekis, Christine Nowotny, Ch. Dadak, L.C. Fuith, H. Gschliesser, E. Burghardt, P. Csaicsich, T. Szepesi, E. Boschitsch, Ch. Büchner, Ch. Bieglmayer, H. Kritz, M. Kleinhans, K. Philipp, M. Metka, H. Janisch, Elisabeth Lasnik, Gabriela Stempel-Smekal, Ch. Nowotny, R. Strigl, W. Lechner, W. Gruber, K.H. Kärcher, G. Lubec, A.R. Schurz, W. Lichtenegger, Heidi Genger, H.D. Fuchs, R. Burmucic, G. Tatra, E. Dworzak, W. Urdl, A. Schaller, R. Spernol, J. Deutinger, G. Freude, W. Stummvoll, and G. Bernaschek

Subjects
Obstetrics and Gynecology, General Medicine
Published
1984

48. Über den Einfluß von 1,8-Dihydroxy-9-anthron (Cignolin) auf die Transplantierbarkeit und den Stoffwechsel von Ehrlich-Ascitestumorzellen

Author

H. Grunicke and H. Berger

Subjects
Chemistry, Drug Discovery, Molecular Medicine, General Medicine, Molecular biology, Genetics (clinical)
Abstract

1. Unter Cignolin wird eine Hemmung der Transplantierbarkeit von Ehrlich-Ascites-Tumorzellen beobachtet. 2. Parallel zum Auftreten der Cytostase ist der Einbau von Vorstufen der DNS, der RNS und des Protein erniedrigt. 3. Wahrend die Glykolyse bei einem Gehalt von 10−3Mol/l an Cignolin deutlich gehemmt wird, ist die Atmung nicht mesbar beeinflust. 4. Eine Reaktion zwischen der DNS und Cignolin in vitro wird beobachtet. Die Befunde werden als Folge einer Bindung des Cignolins an die DNS diskutiert. 5. Die Wirkung des Cignolins gleicht auffallend derjenigen alkylierender Cytostatica, die ebenfalls eine Hemmung der Glykolyse ohne Beeinflussung der Atmung und eine Erniedrigung des Einbaus von Vorstufen der DNS und RNS bewirken.

Published
1967

49. Localization and Regulation of Two NAD Nucleosidases in Ehrlich Ascites Cells

Author

H. P. Beer, V. Gäng, K. W. Bock, R. Kronau, and H. Grunicke

Subjects
Niacinamide, Acid Phosphatase, Centrifugation, Biology, Biochemistry, chemistry.chemical_compound, Microsomes, Animals, Carcinoma, Ehrlich Tumor, N-Glycosyl Hydrolases, Cell Nucleus, Differential centrifugation, chemistry.chemical_classification, Nicotinamide, Adenosine diphosphate ribose, NAD+ nucleosidase, NAD, Nucleotidyltransferases, Molecular biology, Glycerol-3-phosphate dehydrogenase, Enzyme, chemistry, Microsome, NAD+ kinase, Lysosomes, Oxidoreductases, NADP
Abstract

After differential centrifugation of Ehrlich ascites cells by the de Duve method, NAD nuclosidase activities were found in the nuclear and the microsomal fractions, but not in the lysosomal fraction. The nuclear NAD nucleosidase is inhibited 50% by 0.2 mM nicotinamide and is highly specific for β-NAD. Its activity is markedly decreased after DNase treatment; it is associated with chromatin and is very probably identical with an enzyme that polymerizes the adenosine diphosphate ribose moiety of NAD to an acid-insoluble polymer first described in rat liver nuclei by Chambon, Weill, and Mandel. The microsomal NAD nucleosidase is inhibited 50% by 1.2 mM nicotinamide, and splits NAD, NADP and NMN at a ratio of 1:0.5:0.2. NAD and NADP nucleosidase activities are reciprocally inhibited by NADP and NAD. Evidence is presented that the microsomal enzyme is active mainly at the surface of the cell. Nicotinamide concentration may be one factor regulating the nuclear but not the microsomal NAD nucleosidase. Within the cell, NAD is protected by membrane structure from degradation by the microsomal NAD nucleosidase.

Published
1968

50. Untersuchungen Zum Wirkungsmechanismus Von Endoxan

Author

M. Liersch, H. Grunicke, H. Arnold, and Helmut Holzer

Subjects
Pharmacology, Antitumor activity, Hydrolysis, Biochemistry, Chemistry, Structural similarity, chemistry.chemical_element, Glycolysis, NAD+ kinase, Cleavage (embryo), Oxygen, In vitro
Abstract

Hydrolytic cleavage of the esteramidring of endoxan ∗ 0, N′-propylenephosphordiamide' yields 0-(3-aminopropyl)-phosphoromonoamidic acid (A2). In contrast with endoxan this compound A2 (Fig. 1) is characterized by a marked antitumor activity in vitro . The same biochemical effects which have been produced by alkylating agents could be demonstrated with A2. A2 inhibits glycolysis in tumor cells by lowering the NAD concentration. Oxygen consumption of the tumor cells is not influenced by A2. Inhibition of glycolysis and decrease in NAD concentration can only be observed in a weakly acid medium (pH 6.0). At pH 7.4 glycolysis remains unchanged. A structural similarity between A2 and the active antitumor compound present in the serum of endoxan-treated animals is discussed.

Published
1965

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