ABSTRACT
Wnt signaling plays a central role in tissue maintenance and cancer. Wnt activates downstream genes through ß-catenin, which interacts with TCF/LEF transcription factors. A major question is how this signaling is coordinated relative to tissue organization and renewal. We used a recently described class of small molecules that binds tubulin to reveal a molecular cascade linking stress signaling through ATM, HIPK2, and p53 to the regulation of TCF/LEF transcriptional activity. These data suggest a mechanism by which mitotic and genotoxic stress can indirectly modulate Wnt responsiveness to exert coherent control over cell shape and renewal. These findings have implications for understanding tissue morphogenesis and small-molecule anticancer therapeutics.
Subject(s)
Molecular Probes/pharmacology , Protein Serine-Threonine Kinases/metabolism , Small Molecule Libraries/pharmacology , TCF Transcription Factors/antagonists & inhibitors , beta Catenin/antagonists & inhibitors , Animals , Cells, Cultured , Humans , Male , Molecular Probes/chemistry , Small Molecule Libraries/chemistry , TCF Transcription Factors/genetics , TCF Transcription Factors/metabolism , Wnt Signaling Pathway/drug effects , Xenopus , Zebrafish , beta Catenin/genetics , beta Catenin/metabolismABSTRACT
The donor-acceptor (D-A)-type diketopyrrolopyrrole (DPP)-based small molecules (LGC-D117 and LGC-D118) were synthesized and used as the active layer of solution-processable organic field-effect transistors (OFETs). Both LGC-D117 and LGC-D118 contain silaindacenodithiophene as electron-donor units with DPP as an electron-accepting linker, and octylrhodanine as the electron-accepting end group. The molecules were functionalized with different side chains to study their effects on OFET characteristics. LGC-D117 has a simple branched alkyl side chain, whereas LGC-D118 features a bulky siloxane-terminated hybrid alkyl chain. The siloxane side chains of LGC-D118 account for its better crystallinity, leading to significantly high field-effect mobility (max 3.04 cm2 V-1 s-1). In particular, LGC-D118 is well soluble and sustains the high mobility in the environmentally friendly 2-methyltetrahydrofuran solvent with low temperature annealing at 100 °C due to the bulky siloxane-terminated alkyl side chain.