TY - JOUR A1 - Singh, Jasbir A1 - Dani, Harinder M. A1 - Sharma, Reeta A1 - Steinberg, Pablo T1 - Inhibition of the biosynthesis of SRP polypeptides and secretory proteins by aflatoxin B-1 can disrupt protein targeting JF - Cell biochemistry and function N2 - Cell culture and western blotting studies revealed that aflatoxin B-1 (AFB(1)) inhibits the biosynthesis of two of the constituent polypeptides of signal recognition particle (SRP) (SRP54 and 72). SRP escorts polyribosomes carrying signal peptides from free form in the cytosol to the bound form on endoplasmic reticulum (ER) membrane during protein targeting. These effects of AFB(1) on SRP biosynthesis may inhibit the formation of functional SRP Our experiments have further shown that AFB(1) also inhibits the biosynthesis/translocation of a secretory protein, preprolactin, which fails to appear in the lumen of ER consequent to the treatment with this hepatocarcinogen. The results of the experiments presented in this article therefore enable us to infer for the first time that aflatoxin B-1 may inhibit the functioning of SRP as an escort and deplete the ER of polyribosomes for secretory protein synthesis. As these secretory proteins are important components of the plasma membrane, gap junctions and intercellular matrix, their absence from these locations could disturb cell to cell communication leading to tumorigenesis. KW - aflatoxin B-1 KW - SRP KW - protein targeting KW - protein translocation KW - western blotting Y1 - 2005 U6 - https://doi.org/10.1027/cbf.1285 SN - 0263-6484 VL - 24 SP - 507 EP - 510 PB - Wiley CY - Chichester ER - TY - JOUR A1 - Singh, Jasbir A1 - Singh, S. A1 - Dani, H. M. A1 - Sharma, Reeta A1 - Steinberg, Pablo T1 - Interactions of aflatoxin B-1 with SRP components can disrupt protein targeting N2 - Spectrofluorimetric studies have revealed that aflatoxin B-1 (AFB(1)) interacts with signal recognition particle (SRP), which acts as an escort for polyribosomes with signal peptides to be transported and bound to the cytoplasmic face of the endoplasmic reticulum (ER). We further report that the binding of AFB(1) to SRP is selective as it only binds to two (SRP9 and 14) out of its three constituent polypeptides studied. Binding of AFB(1) to proteins is known to alter their conformations. Interactions of AFB(1) with SRP polypeptides may generate structural and functional alterations in this particle and hinder secretory protein synthesis. Copyright (C) 2004 John Wiley Sons, Ltd Y1 - 2005 SN - 0263-6484 ER - TY - JOUR A1 - Fuchs, J. A1 - Teubner, Wera A1 - Steinberg, Pablo T1 - The resistance of intestinal epithelial cells towards the transforming activity of 2-hydroxyamino-1-methyl-6- phenylimidazo[4,5-B]pyridine is accompanied by glutathione S-transferase induction Y1 - 2004 SN - 0028-1298 ER - TY - JOUR A1 - Teubner, Wera A1 - Langheinrich, C. A1 - Seidel, Albrecht A1 - Steinberg, Pablo T1 - Inhibition of p53 transactivation activity does not promote mutagen-induced transformation of IEC-18 Y1 - 2004 SN - 0028-1298 ER - TY - JOUR A1 - Stark, Avishay abraham A1 - Porat, Noga A1 - Volohonsky, Gloria A1 - Konlosh, A. A1 - Bluvshtein, Evgenia A1 - Tubi, C. A1 - Steinberg, Pablo T1 - The role of gamma-glutamyl transpeptidase in the biosynthesis of glutathione Y1 - 2003 ER - TY - JOUR A1 - Okano, J. A1 - Shiota, G. A1 - Matsumoto, K. A1 - Yasui, S. A1 - Kurimasa, A. A1 - Hisatome, I. A1 - Steinberg, Pablo A1 - Murawaki, Y. T1 - Hepatocyte growth factor exerts a proliferative effect on oval cells through the PI3K/AKT signaling pathway Y1 - 2003 ER - TY - JOUR A1 - Bartsch, Ingrid A1 - Zschaler, Ingrid A1 - Haseloff, Monika A1 - Steinberg, Pablo T1 - Establishment of a long-term culture system for rat colon epithelial cells N2 - The aim of this study was to establish a long-term culture. system for rat colon epithelia isolaled by incubating a 4-cm-long rat colon segment cut longitudinally with all ethylenediaminetetraacetic acid [disodium salt]- containing buffer, taken up in conditioned medium from the normal rat kidney fibroblast cell line NRK (i.e., the supernatant Of pure NRK cultures), directly plated on mitomycin C-treated NRK cells and subcultured with conditioned medium from NRK cells. Cells started to migrate out of the crypts shortly after plating them on NRK feeder layers. Some of the crypts fell apart during the isolation procedure. whereas the vast majority of them did it within I to 2 Ill after plating. The cells proliferated extremely slowly but continuously over a period of 4 mo and were epithelial because they expressed cytokeratin 19 and were stained by crystal violet at pH 2.8. In conclusion, the experimental system described ill this study allows to maintain rat colon epithelial cells for up to 4 mo in culture and can be used to Study the effects of a variety of tumor-modulating factors on growth and gene expression of normal colon epithelial cells in vitro Y1 - 2003 UR - http://www.springerlink.com/content/120498/ U6 - https://doi.org/10.1290/0404035.1 SN - 1071-2690 ER - TY - JOUR A1 - Barlow, S. M. A1 - Greig, J. B. A1 - Bridges, J. W. A1 - Carere, A. A1 - Carpy, A. J. A1 - Galli, Corrado L. A1 - Kleiner, J. A1 - Knudsen, I. A1 - Koeter, H. B. A1 - Levy, L. S. A1 - Madsen, C. A1 - Mayer, S. A1 - Narbonne, J. F. A1 - Pfannkuch, F. A1 - Prodanchuk, M. G. A1 - Smith, Mason R. A1 - Steinberg, Pablo T1 - Hazard identification by methods of animal-based toxicology Y1 - 2002 ER - TY - JOUR A1 - Dybing, E. A1 - Doe, J. A1 - Groten, J. A1 - Kleiner, J. A1 - O'Brien, J. A1 - Renwick, A. G. A1 - Schlatter, J. A1 - Steinberg, Pablo A1 - Tritschler, A. A1 - Walker, R. A1 - Younes, M. T1 - Hazard characterisation of chemicals in food and diet : dose response, mechanisms and extrapolation issues Y1 - 2002 ER - TY - JOUR A1 - Volohonsky, Gloria A1 - Tuby, Chen N. Y. H. A1 - Porat, Noga A1 - Wellman-Rousseau, Maria A1 - Visvikis, Athanase A1 - Leroy, Pierre A1 - Rashi, Sharon A1 - Steinberg, Pablo A1 - Stark, Avishay Abraham T1 - A spectrophotometric assay of gamma-glutamylcysteine synthetase and glutathione synthetase in crude extracts from tissues and cultured mammalian cells Y1 - 2002 ER - TY - GEN A1 - Steinberg, Pablo T1 - Only one Component of a holistic Nutrition Policy T1 - Nur ein Baustein einer ganzheitlichen Ernährungspolitik T2 - Fleischwirtschaft Y1 - 2018 SN - 0015-363X VL - 98 IS - 11 SP - 8 EP - 9 PB - Deutscher Fachverlag GmbH CY - Frankfurt am Main ER - TY - GEN A1 - Scholtka, Bettina A1 - Schneider, Mandy A1 - Melcher, Ralph A1 - Katzenberger, Tiemo A1 - Friedrich, Daniela A1 - Berghof-Jäger, Kornelia A1 - Scheppach, Wolfgang A1 - Steinberg, Pablo T1 - A gene marker panel covering the Wnt and the Ras-Raf-MEK-MAPK signalling pathways allows to detect gene mutations in 80% of early (UICC I) colon cancer stages in humans N2 - Background: Very recently a gene marker panel that allows the mutational analysis of APC, CTNNB1, B-RAF and K-RAS was conceived. The aim of the present study was to use the 4-gene marker panel covering the Wnt and Ras-Raf-MEK-MAPK signalling pathways to determine the percentage of sporadic colorectal carcinomas (CRC) carrying at least one of the four above-mentioned genes in a mutated form alone and/or in combination with microsatellite instability (MSI) and to compare the sensitivity of the gene marker panel used in this study with that of gene marker panels previously reported in the scientific literature. Methods: CTNNB1 and B-RAF were screened by PCR-single-strand conformation polymorphism analysis and K-RAS gene mutations by restriction fragment length polymorphism analysis. For the mutational analysis of the APC gene mutation cluster region (codons 1243–1567) direct DNA sequencing was performed. The U.S. National Cancer Institute microsatellite panel (BAT25, BAT26, D2S123, D5S346 and D17S250) was used for MSI analysis. Results: It could be shown that about 80% of early stage CRC (UICC stages I and II) and over 90% of CRC in the UICC stage IV carried at least one mutated gene and/or showed MSI. No significant increase in the gene mutation frequencies could be determined when comparing tumours in the UICC stage I with those in UICC stage IV. Conclusions: When compared with previously published gene marker panels the 4-gene marker panel used in the present study shows an excellent performance, allowing to detect genetic alterations in 80–90% of human sporadic CRC samples analyzed. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - paper 120 KW - Colorectal carcinomas KW - K-RAS KW - Microsatellite instability KW - Oncogenes KW - Tumour suppressor genes Y1 - 2009 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus-44587 ER - TY - JOUR A1 - Kühnel, Dana A1 - Steinberg, Pablo A1 - Scholtka, Bettina T1 - A human-relevant dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PHIP) can induce precancerous lesions in rat intestine after 6 months of exposure Y1 - 2004 SN - 0028-1298 ER - TY - JOUR A1 - Schulz, Tim Julius A1 - Thierbach, Renè A1 - Voigt, Anja A1 - Drewes, Gunnar A1 - Mietzner, Brun A1 - Steinberg, Pablo A1 - Pfeiffer, Andreas F. H. A1 - Ristow, Michael T1 - Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth : Otto Warburg revisited N2 - More than 80 years ago Otto Warburg suggested that cancer might be caused by a decrease in mitochondrial energy metabolism paralleled by an increase in glycolytic flux. In later years, it was shown that cancer cells exhibit multiple alterations in mitochondrial content, structure, function, and activity. We have stably overexpressed the Friedreich ataxia-associated protein frataxin in several colon cancer cell lines. These cells have increased oxidative metabolism, as shown by concurrent increases in aconitase activity, mitochondrial membrane potential, cellular respiration, and ATP content. Consistent with Warburg's hypothesis, we found that frataxin-overexpressing cells also have decreased growth rates and increased population doubling times, show inhibited colony formation capacity in soft agar assays, and exhibit a reduced capacity for tumor formation when injected into nude mice. Furthermore, overexpression of frataxin leads to an increased phosphorylation of the tumor suppressor p38 mitogen-activated protein kinase, as well as decreased phosphorylation of extracellular signal-regulated kinase. Taken together, these results support the view that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals Y1 - 2006 UR - http://www.jbc.org/content/281/2/977.full.pdf+html U6 - https://doi.org/10.1074/jbc.M511064200 ER - TY - JOUR A1 - Thierbach, René A1 - Drewes, Gunnar A1 - Fusser, Markus A1 - Voigt, Anja A1 - Kuhlow, Doreen A1 - Blume, Urte A1 - Schulz, Tim Julius A1 - Reiche, Carina A1 - Glatt, Hansruedi A1 - Epe, Bernd A1 - Steinberg, Pablo A1 - Ristow, Michael T1 - The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals N2 - DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron-sulfur clusters). The nuclear-encoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte- specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA 104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation. Y1 - 2010 UR - http://www.biochemj.org/bj/toc.htm U6 - https://doi.org/10.1042/Bj20101116 SN - 0264-6021 ER - TY - JOUR A1 - Thierbach, René A1 - Blume, Urte A1 - Wolfrum, K. A1 - Drewes, Gunnar A1 - Voigt, Anja A1 - Ristow, Michael A1 - Steinberg, Pablo T1 - Altered carbohydrate metabolism in a tumour developing knock-out mice model Y1 - 2010 UR - http://www.springerlink.com/content/100530 U6 - https://doi.org/10.1007/s00210-010-0508-7 SN - 0028-1298 ER - TY - JOUR A1 - Thierbach, René A1 - Drewes, Gunnar A1 - Fusser, Markus A1 - Wolfrum, Kathrin A1 - Epe, Bernd A1 - Ristow, Michael A1 - Steinberg, Pablo T1 - A role for iron-sulfur cluster proteins in DNA repair Y1 - 2009 UR - http://www.springerlink.com/content/100530 U6 - https://doi.org/10.1007/s00210-009-0404-1 SN - 0028-1298 ER - TY - JOUR A1 - Thierbach, Renè A1 - Schulz, Tim Julius A1 - Isken, Frank A1 - Voigt, Aanja A1 - Mietzner, Brun A1 - Drewes, Gunnar A1 - von Kleist-Retzow, Jürgen-Christoph A1 - Wiesner, Rudolf J. A1 - Magnuson, Mark A. A1 - Puccio, Helene A1 - Pfeiffer, Andreas F. H. A1 - Steinberg, Pablo A1 - Ristow, Michael T1 - Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice N2 - We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation. These animals have a reduced life span and develop multiple hepatic tumors. Livers also show increased oxidative stress, impaired respiration and reduced ATP levels paralleled by reduced activity of iron-sulfur cluster (Fe/S) containing proteins (ISP), which all leads to increased hepatocyte turnover by promoting both apoptosis and proliferation. Accordingly, phosphorylation of the stress-inducible p38 MAP kinase was found to be specifically impaired following disruption of frataxin. Taken together, these findings indicate that frataxin may act as a mitochondrial tumor suppressor protein in mammals Y1 - 2005 ER - TY - JOUR A1 - Thierbach, Rene A1 - Schulz, Tim Julius A1 - Voigt, Aanja A1 - Drewes, Gunnar A1 - Isken, F. A1 - Pfeiffer, Andreas F. H. A1 - Ristow, Michael A1 - Steinberg, Pablo T1 - Targeted disruption of frataxin in hepatocytes causes spontaneous neoplasia accompanied by increased ROS formation Y1 - 2004 SN - 0028-1298 ER - TY - JOUR A1 - Thierbach, Rene A1 - Florian, Simone A1 - Wolfrum, Katharina A1 - Voigt, Anja A1 - Drewes, Gunnar A1 - Blume, Urte A1 - Bannasch, Peter A1 - Ristow, Michael A1 - Steinberg, Pablo T1 - Specific alterations of carbohydrate metabolism are associated with hepatocarcinogenesis in mitochondrially impaired mice JF - Human molecular genetics N2 - Friedreich's ataxia is an inherited neurodegenerative disease caused by the reduced expression of the mitochondrially active protein frataxin. We have previously shown that mice with a hepatocyte-specific frataxin knockout (AlbFxn(-/-)) develop multiple hepatic tumors in later life. In the present study, hepatic carbohydrate metabolism in AlbFxn(-/-) mice at an early and late life stage was analyzed. In young (5-week-old) AlbFxn(-/-) mice hepatic ATP, glucose-6-phosphate and glycogen levels were found to be reduced by similar to 74, 80 and 88%, respectively, when compared with control animals. This pronounced ATP, G6P and glycogen depletion in the livers of young mice reverted in older animals: while half of the mice die before 30 weeks of age, the other half reaches 17 months of age and exhibits glycogen, G6P and ATP levels similar to those in age-matched controls. A key event in this respect seems to be the up-regulation of GLUT1, the predominant glucose transporter in fetal liver parenchyma, which became evident in AlbFxn(-/-) mice being 5-12 weeks of age. The most significant histological findings in animals being 17 or 22 months of age were the appearance of multiple clear cell, mixed cell and basophilic foci throughout the liver parenchyma as well as the development of hepatocellular adenomas and carcinomas. The hepatocarcinogenic process in AlbFxn 2/2 mice shows remarkable differences regarding carbohydrate metabolism alterations when compared with all other chemically and virally driven liver cancer models described up to now. Y1 - 2012 U6 - https://doi.org/10.1093/hmg/ddr499 SN - 0964-6906 VL - 21 IS - 3 SP - 656 EP - 663 PB - Oxford Univ. Press CY - Oxford ER -