Wrenchnolol derivative optimized for gene activation in cells.
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.
Jung
Dongju
D
Institute for Chemical Research and PRESTO/JST, Kyoto University, Uji, Kyoto 611-0011, Japan.
Shimogawa
Hiroki
H
Kwon
Youngjoo
Y
Mao
Qian
Q
Sato
Shin-ichi
S
Kamisuki
Shinji
S
Kigoshi
Hideo
H
Uesugi
Motonari
M
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
D007211:Indoles; C492159:MED23 protein, human; D056892:Mediator Complex; D015534:Trans-Activators; D014157:Transcription Factors; C486112:wrenchnolol; D004247:DNA; D000218:Adamantane