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• W1174449478 abstract "Proc Amer Assoc Cancer Res, Volume 47, 20064328 The pediatric tumor alveolar rhabdomyosarcoma (RMS) exhibits a limited muscle phenotype, but escapes terminal differentiation. Aberrant regulation of myogenesis by the tumor specific PAX3-FKHR and PAX7-FKHR (PAX-FKHR) fusion transcription factors may contribute to this RMS phenotype. To identify the molecular mechanism behind this possible role for PAX-FKHR we characterized their regulation of MyoD, the key regulator of myogenesis, and their influences on myogenic differentiation. We show by reporter assays that MyoD is a transcriptional target of PAX-FKHR, and that PAX-FKHR proteins transactivate MyoD expression through its 258 bp core enhancer. MyoD is a direct target of PAX-FKHR, since in gel shift assays PAX-FKHR physically bind a core enhancer sequence that shows similarity to previously described PAX3 and PAX-FKHR consensus binding sequences. NIH3T3 fibroblasts transduced with PAX3-FKHR stably express MyoD and myogenin proteins. Compared to NIH3T3 cells ectopically expressing MyoD, however, PAX3-FKHR expressing cells are inhibited from terminally differentiating in low-serum growth conditions as shown by the lack of myogenin induction, low myosin heavy chain expression, and absence of myotube formation. Using reporter assays we show that MyoD transcriptional function is attenuated in PAX3-FKHR expressing NIH3T3 cells in differentiation conditions. Posttranslational modification of MyoD, detectable as increased phosphorylation, appears to be the underlying mechanism for the observed inhibition of MyoD function. Studies in progress suggest that these changes in phosphorylation are mediated by FGF signaling. In conclusion, our data demonstrate that in a single experimental system PAX-FKHR can simultaneously induce limited myogenesis by directly activating MyoD expression while preventing complete differentiation. We propose a mechanism whereby the PAX-FKHR proteins commit a yet undefined precursor cell to the myogenic lineage while at the same time inhibit its differentiation into a mature muscle cell, thereby leading to the formation of alveolar RMS. We are currently studying candidate genes from a PAX-FKHR transcriptional signature generated by expression profiling in order to identify pathways that mediate the PAX-FKHR inhibitory effects on myogenesis in alveolar RMS. We believe this work will identify molecular targets for intervention and provide novel options for the treatment of RMS." @default.
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• W1174449478 date "2006-04-15" @default.
• W1174449478 modified "2023-09-24" @default.
• W1174449478 title "The PAX-FKHR fusion proteins transcriptionally activate MyoD while inhibiting its function, thereby inducing a limited myogenic phenotype resembling that of alveolar rhabdomyosarcoma" @default.
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