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.
Hollenbach
A D
AD
Departments of Genetics, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Sublett
J E
JE
McPherson
C J
CJ
Grosveld
G
G
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D056970:Co-Repressor Proteins; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000378:metabolism*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D012208:Rhabdomyosarcoma / Q000235:genetics; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014178:Translocation, Genetic / Q000235:genetics; D015003:Yeasts / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D004268:DNA-Binding Proteins; C491473:Daxx protein, mouse; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D004247:DNA