ARMS is a malignant, skeletal muscle tumor that occurs mainly in older children and adolescents.  Pathological analysis of ARMS tumors indicates that the two most frequent translocations result in the fusion of the transcription factor FOXO1 with Pax3 or Pax7.  The presence of either Pax translocation is indicative of a poor prognosis in metastatic ARMS, with Pax3-FOXO1 positive tumors correlating with the lowest survival rates. Although it is known that Pax3-FOXO1 binds and activates genes containing Pax3 response elements the fusion protein is also capable of regulating genes not normally responsive to wild-type Pax3, suggesting Pax3-FOXO1 gene activation is more complex than originally thought.  To date, a majority of investigations into Pax3-FOXO1 DNA binding and transcriptional activation have focused on the role of the Pax3 DNA-binding domains and make the assumption that the truncated FOXO1 DNA-binding domain is unimportant. We have determined that the truncated FOXO1 DNA-binding domain in Pax3-FOXO1 retains a folding pattern similar to the full-length DNA binding domain using molecular dynamic simulation. In vitro DNA-binding experiments indicate that full-length Pax3-FOXO1 expressed in RH30 cells has the ability to bind a synthetic FOXO1 recognition sequence and a FOXO1 sequence found within the CNR1 proximal promoter.  CNR1 is a confirmed target of Pax3-FOXO1 and is one of several genes in which we have identified a putative FOXO1 recognition sequence adjacent to an identified Pax3-FOXO1 binding site. Taken together, this data indicates that the truncated FOXO1 DNA-binding domain retains activity and contributes to Pax3-FOXO1 targeting of DNA.

Truncated FOXO1 DNA-binding domain in Pax3-FOXO1 contributes to Pax3-FOXO1 DNA binding

243rd National Meeting (2012)

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