Abstract
The Pax3-FKHR fusion protein is present in alveolar rhabdomyosarcoma and results from the t(2;13) (q35;q14) chromosomal translocation. Its oncogenic activity is dependent on a combination of protein-DNA and protein-protein interactions mediated by the Pax3 homeodomain recognition helix. In this report we demonstrate that human Daxx (hDaxx) interacts with Pax3 in vivo and with DNA-bound Pax3 in vitro. This interaction is mediated primarily through the homeodomain recognition helix with the additional involvement of the octapeptide domain and its N-terminal flanking amino acids. Through this interaction hDaxx represses the transcriptional activity of Pax3 by approximately 80%. The Pax3-FKHR fusion is unresponsive to this repressive effect despite an observed endogenous interaction with hDaxx in a rhabdomyosarcoma tumor cell line. Therefore, these data support the model that fusion of FKHR to Pax3 not only adds a strong transactivation domain, but also deregulates transcriptional control of Pax3 by overriding the natural repressive effect of hDaxx.
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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Adaptor Proteins, Signal Transducing
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Amino Acid Sequence
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / isolation & purification
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Carrier Proteins / metabolism*
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Cell Line
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Cloning, Molecular
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Co-Repressor Proteins
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DNA / genetics
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DNA / metabolism
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism*
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Gene Expression Regulation, Neoplastic
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Humans
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Intracellular Signaling Peptides and Proteins*
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Molecular Chaperones
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Molecular Sequence Data
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Molecular Weight
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Nuclear Proteins*
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Oncogene Proteins, Fusion / chemistry
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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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Phosphorylation
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Precipitin Tests
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Protein Binding
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Repressor Proteins / chemistry
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Repressor Proteins / genetics
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Repressor Proteins / isolation & purification
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Repressor Proteins / metabolism*
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Rhabdomyosarcoma / genetics
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Sequence Deletion
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Transcription Factors / metabolism*
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Transfection
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Translocation, Genetic / genetics
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Yeasts / genetics
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Co-Repressor Proteins
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DAXX protein, human
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DNA-Binding Proteins
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Daxx protein, mouse
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FOXO1 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Intracellular Signaling Peptides and Proteins
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Molecular Chaperones
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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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Repressor Proteins
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Transcription Factors
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Pax3 protein, mouse
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DNA