PT  - JOURNAL ARTICLE
AU  - Bane, Fiona T.
AU  - Bannon, John H.
AU  - Pennington, Stephen R.
AU  - Campiani, Giuseppe
AU  - Williams, D. Clive
AU  - Zisterer, Daniela M.
AU  - Mc Gee, Margaret M.
TI  - The Microtubule-Targeting Agents, PBOX-6 [Pyrrolobenzoxazepine 7-[(dimethylcarbamoyl)oxy]-6-(2-naphthyl)pyrrolo-[2,1-<em>d</em>] (1,5)-benzoxazepine] and Paclitaxel, Induce Nucleocytoplasmic Redistribution of the Peptidyl-Prolyl Isomerases, Cyclophilin A and Pin1, in Malignant Hematopoietic Cells
AID  - 10.1124/jpet.108.148130
DP  - 2009 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 38--47
VI  - 329
IP  - 1
4099  - http://jpet.aspetjournals.org/content/329/1/38.short
4100  - http://jpet.aspetjournals.org/content/329/1/38.full
SO  - J Pharmacol Exp Ther2009 Apr 01; 329
AB  - 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 NH2-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 G2/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.