The Pax3-FKHR oncoprotein is unresponsive to the Pax3-associated repressor hDaxx

EMBO J. 1999 Jul 1;18(13):3702-11. doi: 10.1093/emboj/18.13.3702.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / isolation & purification
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cloning, Molecular
  • Co-Repressor Proteins
  • DNA / genetics
  • DNA / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Molecular Chaperones
  • Molecular Sequence Data
  • Molecular Weight
  • Nuclear Proteins*
  • Oncogene Proteins, Fusion / chemistry
  • Oncogene Proteins, Fusion / metabolism*
  • PAX3 Transcription Factor
  • Paired Box Transcription Factors
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / isolation & purification
  • Repressor Proteins / metabolism*
  • Rhabdomyosarcoma / genetics
  • Sequence Deletion
  • Transcription Factors / metabolism*
  • Transfection
  • Translocation, Genetic / genetics
  • Yeasts / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Co-Repressor Proteins
  • DAXX protein, human
  • DNA-Binding Proteins
  • Daxx protein, mouse
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • PAX3 Transcription Factor
  • PAX3 protein, human
  • Paired Box Transcription Factors
  • Repressor Proteins
  • Transcription Factors
  • Pax3 protein, mouse
  • DNA