title: Systematic Protein Level Regulation via Degradation Machinery Induced by Genotoxic Drugs.
abstract: In this study we monitored protein dynamics in response to cisplatin, 5-fluorouracil, and irinotecan with different concentrations and administration modes using "reverse-phase" protein arrays (RPPAs) in order to gain comprehensive insight into the protein dynamics induced by genotoxic drugs. Among 666 protein time-courses, 38% exhibited an increasing trend, 32% exhibited a steady decrease, and 30% fluctuated within 24 h after drug exposure. We analyzed almost 12,000 time-course pairs of protein levels based on the geometrical similarity by correlation distance (dCor). Twenty-two percent of the pairs showed dCor > 0.8, which indicates that each protein of the pair had similar dynamics. These trends were disrupted by a proteasome inhibitor, MG132, suggesting that the protein degradation system was activated in response to the drugs. Among the pairs with high dCor, the average dCor of pairs with apoptosis-related protein was significantly higher than those without, indicating that regulation of protein levels was induced by the drugs. These results suggest that the levels of numerous functionally distinct proteins may be regulated by common degradation machinery induced by genotoxic drugs.
authors.affiliation: Medical Innovation for Advanced Science and Technology program (MIAST), Iwate Medical University , Morioka, Iwate 020-8505, Japan.|Institute for Biomedical Sciences, Iwate Medical University , Yahaba, Iwate 020-8505, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kume
authors.forename: Kazushige
authors.initials: K
authors.lastname: Ishida
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Bioscience and Bioinformatics, Kyushu Institute of Technology , Iizuka, Fukuoka 820-8502, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takemoto
authors.affiliation: Department of Environmental Health, National Institute of Public Health , Wako-shi, Saitama 351-097, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimura
authors.affiliation: National Institutes of Health (NIH) Library, Division of Library Services, Office of Research Services, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: Young
authors.affiliation: Medical Innovation for Advanced Science and Technology program (MIAST), Iwate Medical University , Morioka, Iwate 020-8505, Japan.|Institute for Biomedical Sciences, Iwate Medical University , Yahaba, Iwate 020-8505, Japan.|Department of Surgery, Iwate Medical University School of Dentistry , Morioka, Iwate 020-8505, Japan.
authors.forename: Satoshi S
authors.initials: SS
authors.lastname: Nishizuka
mesh_terms: D017209:Apoptosis; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity*; D004249:DNA Damage; D005472:Fluorouracil / Q000633:toxicity*; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D007976:Leupeptins / Q000494:pharmacology; D009153:Mutagens / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects*; D020543:Proteome / Q000378:metabolism
chemical_list: D007976:Leupeptins; D009153:Mutagens; D061988:Proteasome Inhibitors; D020543:Proteome; D000077146:Irinotecan; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D005472:Fluorouracil; D002166:Camptothecin
keywords: cancer cell; correlation distance (dCor); genotoxic drug; protein dynamics; reverse-phase protein microarray (RPPA)