title: Prolyl isomerase Pin1 regulates doxorubicin-inducible P-glycoprotein level by reducing Foxo3 stability.
abstract: It has been known that the phosphoSer/Thr-Pro-specific peptidyl prolyl cis/trans isomerase Pin1 regulates a variety of intracellular signaling pathways, including the response to the genotoxic drug doxorubicin. Pin1 binds phosphorylated p53 and stabilizes p53 to cause cell cycle arrest and apoptosis quickly in response to doxorubicin. Here we show another mechanism of Pin1 to maintain cell sensitivity to genotoxic stress, irrespective of whether p53 is present or not. In response to the genotoxic drug, Pin1 binds and decreases levels of the phosphorylated Foxo3, the positive transcription factor of P-glycoprotein (P-gp) gene. Through this mechanism of action, Pin1 decreases the level of P-gp and signals the cell to pump the genotoxic drugs out. This shows that Pin1 is implemented in maintaining the susceptibility to the genotoxic drugs by controlling P-gp level as well as p53-dependent apoptosis and cell cycle signaling pathways.
authors.affiliation: Molecular Enzymology, Department of Molecular Cell Science, Graduate School of Agricultural Science, Tohoku University, 1-1 Amamiya, Tsutsumidori, Aoba, Sendai, Miyagi, 981-8555 Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Molecular Enzymology, Department of Molecular Cell Science, Graduate School of Agricultural Science, Tohoku University, 1-1 Amamiya, Tsutsumidori, Aoba, Sendai, Miyagi, 981-8555 Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Bamba
authors.affiliation: Molecular Enzymology, Department of Molecular Cell Science, Graduate School of Agricultural Science, Tohoku University, 1-1 Amamiya, Tsutsumidori, Aoba, Sendai, Miyagi, 981-8555 Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawabe
authors.affiliation: Animal Production Science, Tohoku University, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Biological Science and Technology, Tokyo Kasei University, Kaga 1-18-1, Itabashi, Tokyo 173-8062, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Fujimori
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Human Development and Culture, Fukushima University, Kanayagawa 1, Fukushima, Fukushima 960-1296, Japan.
authors.forename: Chiyoko
authors.initials: C
authors.lastname: Uchida
authors.affiliation: Molecular Enzymology, Department of Molecular Cell Science, Graduate School of Agricultural Science, Tohoku University, 1-1 Amamiya, Tsutsumidori, Aoba, Sendai, Miyagi, 981-8555 Japan. Electronic address: uchidat@biochem.tohoku.ac.jp.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Uchida
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase
keywords: Doxorubicin; Foxo3; P-glycoprotein; Pin1; p53