Abstract
Pax3 is an evolutionarily conserved transcription factor expressed in the lateral dermomyotome, a region that gives rise to limb muscle progenitors. Mutations in Pax-3 account for the mouse mutant Splotch which develops without limb musculature. We demonstrate that Pax3 can inhibit myogenic differentiation of C2C12 myoblasts normally induced by exposure to low serum. Specific missense mutations that affect the DNA binding characteristics of the two distinct DNA binding domains of Pax3 abolish this effect. Furthermore, we show that Pax3 can inhibit myogenic differentiation of 10T1/2 fibroblasts transfected with MyoD, but not of 10T1/2 cells transfected with myogenin. This anti-myogenic property is shared by a PAX3-forkhead fusion protein resulting from a t(2;13) chromosomal translocation found in pediatric alveolar rhabdomyosarcomas. These results suggest that Pax3 may suppress the terminal differentiation of migrating limb myoblasts and that the PAX3-forkhead fusion may contribute to the phenotype of alveolar rhabdomyosarcoma by preventing terminal differentiation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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Binding Sites
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Cell Differentiation / drug effects
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Cells, Cultured
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Chromosomes, Human, Pair 13 / ultrastructure
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Chromosomes, Human, Pair 2 / ultrastructure
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / pharmacology*
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Extremities / embryology
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Forkhead Transcription Factors
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Humans
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Mice
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Mice, Mutant Strains
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Molecular Sequence Data
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Muscles / cytology*
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Nuclear Proteins / genetics
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Oncogene Proteins, Fusion / metabolism
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PAX3 Transcription Factor
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Paired Box Transcription Factors
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Recombinant Fusion Proteins / metabolism
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Rhabdomyosarcoma, Alveolar / genetics
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Rhabdomyosarcoma, Alveolar / pathology
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Stem Cells / cytology
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Stem Cells / drug effects*
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Transcription Factors / genetics
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Transfection
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Translocation, Genetic
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Waardenburg Syndrome / genetics
Substances
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Nuclear Proteins
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Oncogene Proteins, Fusion
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PAX3 Transcription Factor
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PAX3 protein, human
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Paired Box Transcription Factors
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Recombinant Fusion Proteins
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Transcription Factors
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Pax3 protein, mouse