Transcriptional Activation by Pax3‐FOXO1 is influenced by the presence of FOXO1 promoter elements

Abstract

The translocation of FOXO1 with either Pax3 or Pax 7 has been implicated in the development of Alveolar Rhabdomyosarcoma (ARMS). These translocations yield chimeric proteins containing amino‐terminal portions of either Pax transcription factor fused to carboxy terminal regions FOXO1. Cellular transformation by Pax3‐FOXO1 is dependent on the presence of the FOXO transactivation domain; by contrast, little attention has been paid to the DNA‐binding ability of FOXO1 fusions. The FOXO1 fusions retain a significant portion of the conserved DNA‐binding domain necessary for DNA contact, and Pax3‐FOXO1 can interact with FOXO1 recognition sequences in vitro. The objective of this study to determine if FOXO1 recognition sequences influence Pax3‐FOXO1 gene targeting and transcriptional activation. We examined the proximal promoter region of putative Pax3‐FOXO1 targets and determined that Pax3 and FOXO1 recognition sequences could be found in close proximity in 75% of these genes. We further examined four known targets of Pax3‐FOXO1 and again identified FOXO1 elements adjacent to the identified Pax3‐FOXO1 binding site. Of these, CNR1, is also a transcriptional target of FOXO1 and was therefore chosen for further study. These data indicate that FOXO1 fusions may target genes normally regulated by FOXO1 as well as those targeted by their fusion partner.