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

Youbin Zhang, Joel Schwartz, Chiayeng Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The alveolar rhabdomyosarcoma-associated t(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.

Original languageEnglish (US)
Pages (from-to)370-383
Number of pages14
JournalInternational Journal of Clinical and Experimental Pathology
Volume2
Issue number4
StatePublished - 2009

Keywords

  • Fusion oncoprotein
  • Nude mice
  • Rhabdomyosarcoma
  • Tumorigenesis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology

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