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RADIOBIOLOGY 103 calf serum, 2.5% PHA (phytohaemagglutinin), anibiotic solution and incubated for 72 h at 37 o C and 5% CO 2 . Lymphocyte preparations for micronuclei analysis were prepared according to the standard method of Fenech [2]. As shown in Fig., temperature of pre-irradiation incubation as well as that during exposure exerts an effect on the frequency of radiation-induced micronuclei in human peripheral blood lymphocytes. The highest frequency of micronuclei is observed for blood samples incubated at 37 o C before and during irradiation in vitro with doses of 2 and 2.7 Gy. Further work is aimed at elucidation of the mechanism of this effect. The work was supported by the Polish Ministry of Scientific Research and Information Technology statutory grant for the INCT. References [1]. Bajerska A., Liniecki J.: Int. J. Radiat. Biol., 16, 483-493 (1969). [2]. Fenech M.: Mutat. Res., 285, 35-44 (1993). EGF RECEPTOR KINASE ACTIVITY IS REQUIRED FOR EFFICIENT DOUBLE STRAND BREAK REJOINING IN X-IRRADIATED HUMAN GLIOMA M059 CELLS Iwona Grądzka, Barbara Sochanowicz, Irena Szumiel tive to X-radiation due to the lack of a catalytic subunit of DNA-dependent protein kinase (DNA-PK cs ). Tyrphostin AG 1478 was used as a specific inhibitor to block EGFR tyrosine kinase activity. We found that the total cellular level of EGFR is 3-fold higher in M059 J than in M059 K cells. This correlates with higher resistance of M059 J to tyrphostin AG 1478. Addition of EGF to the cell cultures results both in the increase of phosphorylation status of EGFR (at the position Y1068) and in the receptor translocation to the nuclei. In HeLa cells the EGFR autophosphorylation is the main effect of the stimulation with the ligand. On the contrary, in M059 K and J cells, EGFR translocation to the nuclei prevails over autophosphorylation. Tyrphostin AG 1478 prevents the EGF-induced receptor accumulation in the nuclei of M059 K and J cells (not shown). Thus, the kinase activity of EGFR enables the receptor translocation to the nuclei in the gliomas. In accordance with the results of Dittmann et al. [4], in M059 K cells X-irradiation induces EGFR translocation to the nuclei. This process can be prevented by tyrphostin AG 1478 (Fig.1A). In M059 J cells no accumulation of EGFR in the nuclei is observed following X-irradiation (Fig.1B). The data indicate that the kinase activity of EGFR and the presence of DNA-PK cs , lacking in M059 J cells, are required for EGFR translocation to the nuclei following the DNA damage. Double strand break (DSB) rejoining after X-irradiation is faster in M059 K than in M059 J cells because of a defect in a nonhomologous DNA end- -joining (NHEJ) in the latter cell line (lack of an Fig.1. Accumulation of EGFR in the nuclei of M059 K (A) and M059 J (B) cells after X-irradiation with 10 Gy and the effect of tyrphostin AG 1478 (T) on this process. The epidermal growth factor (EGF) receptor (EGFR) is a mediator of both proliferative and survival signals in mammalian cells (reviewed in [1]). Nuclear translocation of EGFR was observed after the ligand binding as well as following the ligand-independent activation. The latter was always linked to exposure to genotoxic stress and it was speculated that it is important for regulation of DNA repair processes [2]. We investigated the effect of EGF and X-irradiation on EGFR activation and translocation to the nuclei in two related human glioma cell lines M059 K and M059 J, the latter highly sensi- important NHEJ component – DNA-PK cs ) [3]. Tyrphostin AG 1478 slows down the DSB rejoining in M059 K and has no effect in M059 J cells. This suggests a direct link between EGFR kinase activity and DNA-PK-dependent DSB rejoining and is consistent with observation of other authors [3]. The work was supported by the Polish Ministry of Scientific Research and Information Technology – grant No. 3 P05A 013 23. References [1]. Amorino G.P., Hamilton V.M., Valerie K., Dent P., Lammering G., Schmidt-Ulrich R.K.: Mol. Biol. Cell, 13, 2233-2244 (2002). [2]. Harari P.M., Huang S.M.: Semin. Radiat. Oncol., 11, 281-289 (2001). [3]. Anderson C.W., Dunn J.J., Freimuth P.I., Galloway A.M., Allalunis-Turner M.J.: Radiat. Res., 156, 2-9 (2001). [4]. Dittmann K., Mayer C., Fehrenbacher B., Schaller M., Raju U., Milas L., Chen D.J., Kehlbach R., Rodemann H.P.: J. Biol. Chem., 280, 31182-31189 (<strong>2005</strong>).
104 RADIOBIOLOGY DNA INTER-STRAND CROSSLINKS ARE INDUCED IN CELLS PRE-LABELLED WITH 5-BROMO-2’-DEOXYURIDINE AND EXPOSED TO UVC RADIATION Andrzej Wójcik 1,2/ , Agnieszka Bochenek 1/ , Anna Lankoff 1/ , Halina Lisowska 1/ , Anna Padjas 3/ , Clemens von Sonntag 4,5/ , Günter Obe 6/ 1/ Institute of Biology, Świętokrzyska Academy, Kielce, Poland 2/ Institute of Nuclear Chemistry and Technology, Warszawa, Poland 3/ Holycross Cancer Center, Kielce, Poland 4/ The Max Planck Institute for Bioinorganic Chemistry, Mülheim an der Ruhr, Germany 5/ Leibniz-Institut für Oberflächenmodifizierung (IOM), Leipzig, Germany 6/ Institute of Genetics, University of Duisburg-Essen, Essen, Germany It has been observed previously that 5-bromo-2’-deoxyuridine (BrdU) potentiates the effect of UVC radiation on the level of sister chromatid exchanges. It is not known which type of DNA damage is responsible for this enhancing effect and we have proposed this to be the DNA inter-strand crosslink (ICL) [1] which, theoretically, may arise in cells that are labelled with BrdU for one round of replication and exposed to UVC radiation. This notion was based on the fact that irradiation of BrdU-labelled DNA with UV leads not only to the formation of a uracilyl radical but also of a bromine atom which can oxidise a purine base of the DNA strand opposed to the uracilyl radical. Thus, two radicals at opposing strands are formed and this can easily lead to the formation of an ICL. The aim of the present investigation was to verify if ICLs are indeed formed in this irradiation scenario. CHO-K1 cells were pre-labelled with BrdU and exposed to UVC. ICLs were detected by the modified version of the comet assay that relies on the reduction of induced DNA migration in the agarose gel. Carboplatin was used as a positive control. The results fully supported this hypothesis: exposure to BrdU+UVC reduced the level of damage induced by gamma radiation and measured in the comet assay in a manner similar to carboplatin, a platinum compound which is a potent inducer of both ICLs and intra-strand crosslinks. In order to confirm the results of the comet assay in a different system, we have tested the sensitivity of CL-V4B cells towards BrdU+UVC. These cells have a mutated Rad51C paralog, a key enzyme in the homologous recombination repair [2,3]. Due to this, they are highly sensitive to ICLs [4]. The observation of a high level (as compared to the wild type cells) of chromosomal damage in CL-V4B cells exposed to BrdU+UVC and mitomycin C, but not to UVC alone, substantiates the results obtained with the comet assay (cf. Fig.). Fig. Percent of cells with chromosomal aberrations following treatment with UVC (60 J m –2 ), BrdU+UVC (3 J m –2 ) and mytomycin C – MMC (0.2 µM) in the Rad51C mutants (CL-V4B) and wild type cells (V79B). Error bars represent standard deviations from the results of three independent experiments. * – difference between cell lines significant with p
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ANNUAL REPORT 2005 50 years in the
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CONTENTS GENERAL INFORMATION 9 MANA
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DETERMINATION OF CADMIUM, LEAD, COP
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NUCLEONIC CONTROL SYSTEMS AND ACCEL
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GENERAL INFORMATION 9 GENERAL INFOR
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MANAGEMENT OF THE INSTITUTE 11 MANA
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MANAGEMENT OF THE INSTITUTE 13 •
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SCIENTIFIC STAFF 15 5. Danilczuk Ma
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RADIATION CHEMISTRY AND PHYSICS, RA
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20 RADIATION CHEMISTRY AND PHYSICS,
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THE INCT PUBLICATIONS IN 2005 163 V
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NUKLEONIKA 169 NUKLEONIKA THE INTER
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NUKLEONIKA 171 7. Influence of time
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INTERVIEWS IN 2005 173 INTERVIEWS I
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CONFERENCES ORGANIZED AND CO-ORGANI
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EDUCATION 209 EDUCATION Ph.D. PROGR
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RESEARCH PROJECTS AND CONTRACTS 211
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RESEARCH PROJECTS AND CONTRACTS IAE
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LIST OF VISITORS TO THE INCT IN 200
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LECTURES AND SEMINARS DELIVERED OUT
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LECTURES AND SEMINARS DELIVERED OUT
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AWARDS IN 2005 221 AWARDS IN 2005 1
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INSTRUMENTAL LABORATORIES AND TECHN
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INDEX OF THE AUTHORS 235 Lisowska H
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