Pharmacological inhibition of the Janus Kinases enhances ASCL1 protein stability and transcriptional activity.

BACKGROUND: Achaete-Scute complex homolog 1 (ASCL1) is a multi-faceted pro-neural transcription factor, playing a role in several processes during embryonic development and into adulthood, including neural progenitor proliferation and neuronal differentiation. This versatility is achieved through tightly controlled expression of ASCL1, either via integrating intracellular signalling cues or stabilisation at the protein level. The role of kinases in ASCL1-mediated neurogenesis is emerging, but to date few kinases have been attributed to act directly or indirectly on ASCL1. METHODS AND RESULTS: To address this, we designed a cell-based high-throughput screen to identify kinase inhibitors that enhance ASCL1 protein levels. From this screen, two kinase inhibitors were identified to increase ASCL1 stability and transcriptional activity, and subsequent validation indicated that the effect was driven indirectly through Janus kinase family members. CONCLUSIONS: These compounds may serve as useful tools for further investigating the role played by kinases in regulating neurogenesis and ultimately enable better understanding of how ASCL1 integrates different signalling cues to orchestrate with high precision the differentiation of progenitor cells into neurons.