Original Article Comparative analysis of paired- and homeodomain-specific roles in PAX3-FKHR oncogenesis
Youbin Zhang, Joel Schwartz and Chiayeng Wang
Center for Molecular Biology of Oral Diseases, Department of Oral Medicine and Diagnosis and Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
Received 17 November 2008; Accepted 21 November 2008; Available online 01 December 2008
Abstract: The alveolar rhabdomyosarcoma associated 2;13 chromosomal translocation produces an oncogenic fusion transcription factor PAX3-FKHR that combines the N-terminal DNA binding domains (paired domain and homeodomain) of PAX3 with the C-terminal activation domain of FKHR. In the context of PAX3-FKHR, the two DNA binding domains can work either cooperatively or autonomously in regulating gene transcription. The latter is a gain-of-function unique to the fusion protein. The biological activities driven by the individual DNA binding domain remains poorly defined. In this study, we express PAX3-FKHR mutants that contain only a single functional DNA binding domain into C2C12 myoblasts, and measured the in vitro and in vivo behaviors of these cells. We show that only the homeodomain-specific PAX3-FKHR mutant recapitulates the in vitro transformation properties of the wild type fusion protein. However, despite the differential responses in vitro, both the paired domain- and the homeodomain-specific PAX3-FKHR mutants promote tumor development from myoblasts in vivo. Our results suggest an important role for the gain of the paired domain- and the homeodomain-transcription activities in the PAX3-FKHR malignant transformation process. (IJCEP811007).