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Int J Clin Exp Pathol 2(4),370-383;2009

Original Article
Comparative analysis of paired- and homeodomain-specific roles in PAX3-FKHR

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).

Key Words: Fusion oncoprotein, rhabdomyosarcoma, tumorogenesis, nude mice

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Address all correspondence to: Chiayeng Wang,PhD, CMBOD, University of Illinois at Chicago, 801 South Paulina Street, Chicago, IL 60612,
Tel: 312-996-4530, Fax: 312-413-1604, E-mail: chiayeng@uic.edu