TUMOR-SPECIFIC PAX3-FKHR TRANSCRIPTION FACTOR, BUT NOT PAX3, ACTIVATES THE PLATELET-DERIVED GROWTH-FACTOR-ALPHA RECEPTOR

The t(2;13) chromosomal translocation occurs at a high frequency in al veolar rhabdomyosarcoma, a common pediatric tumor of muscle. This tran slocation results in the production of a chimeric fusion protein deriv ed from two developmentally regulated transcription factors, PAX3 and FKHR. The two DNA binding modules, the paired domain and the homeodoma in, of PAX3 are fused in frame to the transactivation domain of FKHR. Previously, tumor-specific PAX3-FKHR has been shown to bind to DNA seq uences normally recognized by wild-type PAX3 and to exhibit relatively enhanced transcriptional activity. The DNA binding sites used to demo nstrate that PAX3-FKHR is a more potent transcriptional activator than PAX3 have included recognition sequences for the paired domain of PAX 3. In this report, we demonstrate the ability of PAX3-FKHR to activate the product of a growth control gene, platelet-derived growth factor alpha receptor (PDGF alpha R), by recognizing a paired-type homeodomai n binding site located in the PDGF alpha R promoter. PAX3 alone cannot mediate transcriptional activation of this promoter under the conditi ons tested. This provides the first evidence that chromosomal transloc ation results in altered target gene specificity of PAX3-FKHR and sugg ests a transcriptional target that may play a significant role in onco genic activity and rhabdomyosarcoma development.