Identification of Novel Regulators of Numb Alternative Splicing

Alternative splicing (AS) is a post-transcriptional mechanism resulting in the production of multiple mRNA and protein isoforms from a single gene. The endocytic adaptor protein Numb undergoes AS of exon 9 (E9) to produce two developmentally regulated isoforms: E9-included products are expressed in progenitors while E9-excluded products are expressed in differentiated cells. A global analysis of AS events in multiple cancers identified a shift in Numb transcript and protein expression from the E9-excluded to the E9-included isoform, suggesting that misregulation of the mechanisms that control E9 inclusion may play a role in tumorigenesis. Here we describe a potential mechanism by which the splicing regulators PTBP1 and ASF/SF2 and the MAPK/ERK signalling pathway contribute to cancer development by regulating the observed Numb AS switch. We also found evidence of a functional role for the Numb AS switch in cancer, through alterations in Notch signalling target gene expression due to MAPK/ERK suppression.M.Sc.2016-05-19 00:00:0