The hunt for a PAX3‐FOXO1 motif (939.4)

Abstract

Alveolar Rhabdomyosarcoma (ARMS) patients carrying a chromosomal translocation of PAX3 and FOXO1 have the highest mortality rates, indicating the importance of understanding how this transcription factor influences gene expression. Many studies have been performed to identify PAX3‐FOXO1 target genes and while some overlapping gene sets have been identified, there exists great variation in the genes identified. The search for these target genes is hampered by a lack of understanding of the full DNA‐binding capabilities of this fusion protein. We have examined the truncated FOXO1 DNA‐binding domain in PAX3‐FOXO1 and found that it retains activity, but does not have the same sequence specifications for binding as full length FOXO1. A search of 1463 PAX3‐FOXO1 putative binding sites revealed that 37% contained both a PAX3 paired domain and FOXO1 recognition sequence within close proximity. The sequences containing the dual motif mapped to 160 genes with the most interesting of these known to be regulated by PAX3‐FOXO1 such as MET or upregulated in response to PAX3‐FOXO1 expression such as ABAT and PBK. Here we present additional data exploring the sequence variations on the PAX3 and FOXO1 recognition sequences found within Pax3‐FOXO1 putative binding sites as well as in vitro confirmation of the interaction. Grant Funding Source: Supported by NIH SC2GM095430