21 June 2010
Anna Philpott
Department of Oncology
MRC Research Centre
University of Cambridge
Proneural transcription factors such as Neurogenins and Mash1 play central roles in regulating the balance between proliferation and differentiation in a wide range of tissues including the brain and pancreas, yet little is known about their post-translational regulation. We have taken a biochemical approach side by side with in vivo functional analysis to address this problem.
We have uncovered new mechanisms of post-translational control of Neurogenin (Ngn) that links its activity to cell cycle progression. Firstly, we see direct regulation of Ngn protein stability by cyclin-dependent kinase inhibitors. Moreover, we see that Ngn is phosphorylated on multiple serine-proline pairs by cell cycle-regulated kinases, and that this phosphorylation inhibits the activity of the protein. This effect seems to be semi-quantitative; the more sites that are phosphorylated, the greater the inhibition of transcriptional activity, potentially linking enhanced cell cycling directly to an inhibition of Ngn2-driven differentiation. Mechanistically, we see that phosphorylation regulates Ngn2 binding to its heterodimeric binding E protein partner, controlling chromatin association and transcriptional activity. We speculate that multi-site phosphorylation can act as a "quantitative" sensor of cell cycle length and this is translated into regulation of protein stability and transcriptional activity, directly linking cell cycle with the decision to divide or differentiate.