title: Genome-wide drug-induced haploinsufficient screening of fission yeast for identification of hydrazinocurcumin targets.
abstract: Hydrazinocurcumin (HC), a synthetic derivative of curcumin, has been reported to inhibit angiogenesis via unknown mechanisms. Understanding the molecular mechanisms of the drug's action is important for the development of improved compounds with better pharmacological properties. A genomewide drug-induced haploinsufficiency screening of fission yeast gene deletion mutants has been applied to identify drug targets of HC. As a first step, the 50% inhibition concentration (IC50) of HC was determined to be 2.2 microM. The initial screening of 4,158 mutants in 384-well plates using robotics was performed at concentrations of 2, 3, and 4 microM. A second screening was performed to detect sensitivity to HC on the plates. The first screening revealed 178 candidates, and the second screening resulted in 13 candidates, following the elimination of 165 false positives. Final filtering of the condition-dependent haploinsufficient genes gave eight target genes. Analysis of the specific targets of HC has shown that they are related to septum formation and the general transcription processes, which may be related to histone acetyl transferase. The target mutants showed 65% growth inhibition in response to HC compared with wild-type controls, as shown by liquid culture assay.
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 305-333, Korea.
authors.forename: Seung Tae
authors.initials: ST
authors.lastname: Baek
authors.forename: Dong-Uk
authors.initials: DU
authors.lastname: Kim
authors.forename: Sangjo
authors.initials: S
authors.lastname: Han
authors.forename: Im Sun
authors.initials: IS
authors.lastname: Woo
authors.forename: Miyoung
authors.initials: M
authors.lastname: Nam
authors.forename: Lila
authors.initials: L
authors.lastname: Kim
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Heo
authors.forename: Hyemi
authors.initials: H
authors.lastname: Lee
authors.forename: Hye-Rim
authors.initials: HR
authors.lastname: Hwang
authors.forename: Shin-Jung
authors.initials: SJ
authors.lastname: Choi
authors.forename: Misun
authors.initials: M
authors.lastname: Won
authors.forename: Minho
authors.initials: M
authors.lastname: Lee
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Sunghou
authors.initials: S
authors.lastname: Lee
authors.forename: Ho-Jung
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Pil Jae
authors.initials: PJ
authors.lastname: Maeng
authors.forename: Hee-Moon
authors.initials: HM
authors.lastname: Park
authors.forename: Youngwoo
authors.initials: Y
authors.lastname: Park
authors.forename: Dongsup
authors.initials: D
authors.lastname: Kim
authors.forename: Kwang-Lae
authors.initials: KL
authors.lastname: Hoe
mesh_terms: D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D017353:Gene Deletion; D016681:Genome, Fungal; D006238:Haploidy; D006579:Heterozygote; D006834:Hydrazines / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D006834:Hydrazines; D029702:Schizosaccharomyces pombe Proteins; C475807:hydrazinocurcumin; D003474:Curcumin