title: The microtubule-targeting agents, PBOX-6 [pyrrolobenzoxazepine 7-[(dimethylcarbamoyl)oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine] and paclitaxel, induce nucleocytoplasmic redistribution of the peptidyl-prolyl isomerases, cyclophilin A and pin1, in malignant hematopoietic cells.
abstract: Microtubule assembly and disassembly is required for the maintenance of cell structure, mobility, and division. However, the cellular and biochemical implications of microtubule disruption are not fully understood. Using a proteomic approach, we found that the peptidyl-prolyl isomerase, cyclophilin A, was increased in plasma membrane extracts from chronic myeloid leukemia cells after microtubule disruption. In addition, we found that two peptidyl-prolyl isomerases, cyclophilin A and pin1, are overexpressed up to 10-fold in hematological malignancies compared with normal peripheral blood mononuclear cells. Although previous reports suggest that cyclophilin A is localized to the cytosol of mammalian cells, we found that cyclophilin A and pin1 are both localized to the nucleus and nuclear domains in hematopoietic cells. Microtubule disruption of hematopoietic cells caused a dramatic subcellular redistribution of cyclophilin A and pin1 from the nucleus to the cytosol and plasma membrane. We suggest that this accounts for the increased cyclophilin A at the plasma membrane of chronic myeloid leukemia cells after microtubule disruption. The subcellular redistribution of cyclophilin A and pin1 occurred in a c-Jun NH(2)-terminal kinase- and serine protease-dependent manner. Moreover, the altered subcellular localization of the peptidyl-prolyl isomerases occurred in a dose- and time-dependent manner after microtubule disruption and was found to correlate with G(2)/M arrest and precede induced cell death. These results suggest that the function of peptidyl-prolyl isomerases may be influenced by microtubule dynamics throughout the cell cycle, and their altered localization may be an important part of the mechanism by which microtubule-disrupting agents exert their cytostatic effects.
authors.affiliation: School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Fiona T
authors.initials: FT
authors.lastname: Bane
authors.forename: John H
authors.initials: JH
authors.lastname: Bannon
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Pennington
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campaini
authors.forename: D Clive
authors.initials: DC
authors.lastname: Williams
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Mc Gee
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D021984:Cyclophilin A / Q000378:metabolism*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006868:Hydrolysis; D008870:Microtubules / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010077:Oxazepines / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D010449:Peptide Mapping; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D016622:Silver Staining; D014357:Trypsin / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010077:Oxazepines; D011758:Pyrroles; D014357:Trypsin; D021984:Cyclophilin A; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C418868:PBOX-6; D017239:Paclitaxel