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dc.contributor.advisor Mueller, Gerhard Anton Prof. Dr. de
dc.contributor.advisor Dihazi, Hassan Dr. de
dc.contributor.author Agarwal, Nitin Kumar de
dc.date.accessioned 2013-01-31T07:57:31Z de
dc.date.available 2013-01-31T07:57:31Z de
dc.date.issued 2007-06-11 de
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-000D-F227-3 de
dc.format.mimetype application/pdf de
dc.language.iso eng de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ de
dc.title Proteome-wide Identification of New Molecular Targets Affected by Methotrexate in Acute Promyelocytic Leukaemia Cell Line de
dc.type doctoralThesis de
dc.title.translated Proteome-wide Identification of New Molecular Targets Affected by Methotrexate in Acute Promyelocytic Leukaemia Cell Line de
dc.contributor.referee Hardeland, Rüdiger Prof. Dr. de
dc.date.examination 2007-05-02 de
dc.subject.dnb 610 Medizin, Gesundheit de
dc.subject.gok MED 344 de
dc.subject.gok MED 351 de
dc.subject.gok MED 353 de
dc.subject.gok MED 424 de
dc.description.abstracteng Methotrexate (MTX) was first introduced as a cytotoxic agent that inhibits nucleotide biosynthesis in various cancer disorders. Accumulating evidences suggest that MTX inhibits the proliferation of malignant cells by inhibiting 5-aminoimidazole-4-carbox-amide ribonucleotide transformylase, isoprenylcysteine carboxyl methyltransferase and NF-kappaB transcription factor. These observations indicate that MTX could have additional molecular targets that are therefore unappreciated. To get insights into the complex molecular mechanisms of MTX induced apoptosis in acute promyelocytic leukemia cells (HL 60), we conducted an investigation incorporating cysteine labeled differential in gel electrophoresis combined with mass spectrometry. Initial experimental analysis revealed that 24 proteins were differentially expressed (p > 0.05) in HL 60 cell proteome after addition of 2.5 µM MTX for 72 hours. The majority of MTX induced proteins were ascribed to the endoplasmic reticulum (ER) chaperones, glycolytic enzymes and the mitochondrial transmembrane electron transport system (MTETS). In particular, we noted that three structural alpha4, alpha5, alpha7; a non-catalytically beta3 and two 26S regulatory proteasome subunits were significantly down regulated in MTX treated HL 60 cell. We further showed in HL 60 cells that MTX induces ER chaperones, suppresses the NF-kappaB subunit p65, disturbs the mitochondrial transmembrane potential (Äøm) and generates reactive oxygen species (ROS) in a time dependent manner. All together, our findings revealed that MTX alter the level of a variety of proteins involved in the NF-kappaB associated proteasome complex formation, ER stress, and the MTETS. Their identification as molecular targets of MTX may provide new impulse in the understanding of apoptotic activities in acute promyelocytic leukaemia cell line. de
dc.contributor.coReferee Doenecke, Detlef Prof. Dr. de
dc.contributor.thirdReferee Hirsch-Ernst, Karen Dr. de
dc.subject.topic Mathematics and Natural Science de
dc.subject.eng Acute Promyelocytic Leukaemia cells de
dc.subject.eng Methotrexate de
dc.subject.eng Proteomics de
dc.subject.eng Cysteine labelled differential in-gel electrophoresis de
dc.subject.eng Proteasome subunits de
dc.subject.bk 44.00 de
dc.subject.bk 44.03 de
dc.subject.bk 44.13 de
dc.subject.bk 44.38 de
dc.subject.bk 44.41 de
dc.subject.bk 44.81 de
dc.identifier.urn urn:nbn:de:gbv:7-webdoc-1490-4 de
dc.identifier.purl webdoc-1490 de
dc.identifier.ppn 565556533 de

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