The Pax3-FKHR oncoprotein is unresponsive to the Pax3-associated repressor hDaxx
Copyright policy )The Pax3-FKHR oncoprotein is unresponsive to the Pax3-associated repressor hDaxx
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.
- St. Jude Children's Research Hospital United States
Oncogene Proteins, Fusion, Forkhead Box Protein O1, Molecular Sequence Data, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Forkhead Transcription Factors, DNA, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Molecular Weight, Humans, Paired Box Transcription Factors, Amino Acid Sequence, Cloning, Molecular, Carrier Proteins, Co-Repressor Proteins, PAX3 Transcription Factor, Adaptor Proteins, Signal Transducing, Molecular Chaperones
Oncogene Proteins, Fusion, Forkhead Box Protein O1, Molecular Sequence Data, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Forkhead Transcription Factors, DNA, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Molecular Weight, Humans, Paired Box Transcription Factors, Amino Acid Sequence, Cloning, Molecular, Carrier Proteins, Co-Repressor Proteins, PAX3 Transcription Factor, Adaptor Proteins, Signal Transducing, Molecular Chaperones
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