title: Wrenchnolol derivative optimized for gene activation in cells.
abstract: Naturally occurring transcription factors usually have two independent domains, a DNA-binding domain and an activation domain. In designing a synthetic small molecule that mimics a transcription factor, each of the two domains needs to be replaced by small-molecule counterparts. Results of the present study show that derivatives of wrenchnolol, a synthetic molecule that interacts with Sur-2 coactivator, serve as activation modules and stimulate gene transcription in vitro and in cells when tethered to a DNA-binding molecule. Thirteen derivatives of wrenchnolol were chemically synthesized and tested for their ability to activate transcription in vitro and in cells. When tethered to the GAL4 DNA-binding domain, one derivative increased transcription of a GAL4-responsive reporter gene in cells 9-fold. This optimized derivative also induced up to 45% myogenesis of C2C12 cells when tethered to the DNA-binding domain of myogenic transcription factor MyoD. This optimized derivative may serve as a starting point for designing biological tools or components of fully synthetic transcription factors that permit selective up-regulation of genes.
authors.affiliation: Institute for Chemical Research and PRESTO/JST, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Dongju
authors.initials: D
authors.lastname: Jung
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimogawa
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.forename: Qian
authors.initials: Q
authors.lastname: Mao
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Sato
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Hideo
authors.initials: H
authors.lastname: Kigoshi
authors.forename: Motonari
authors.initials: M
authors.lastname: Uesugi
mesh_terms: D000218:Adamantane / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D032701:Biomimetics; D002454:Cell Differentiation; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D056892:Mediator Complex; D032446:Myoblasts / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D007211:Indoles; C492159:MED23 protein, human; D056892:Mediator Complex; D015534:Trans-Activators; D014157:Transcription Factors; C486112:wrenchnolol; D004247:DNA; D000218:Adamantane