Guilt by association: PAX3-FOXO1 regulates gene expression through selective destabilization of the EGR1 transcription factor.
Human cancer cells frequently harbor chromosomal translocations that create chimeric fusion genes. The t(2;13) translocation is characteristic of the pediatric muscle tumor, alveolar rhabdomyosarcoma, and produces the chimeric transcription factor, PAX3-FOXO1, that contains the DNA binding elements of PAX3 and the transcriptional activation domain of FOXO1. Experiments designed to determine how PAX3-FOXO1 expression contributes to the development of muscle cell-derived tumors resulted in the discovery that the fusion protein misregulates gene expression and interrupts myogenic differentiation through a unique gain of function mechanism. These results yield new insight into how tumor-associated genetic alterations increase the likelihood of cancer formation and may lead to new therapeutic approaches.
Roeb
Wendy
W
The Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California, USA.
Boyer
Antonia
A
Cavenee
Webster K
WK
Arden
Karen C
KC
D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D008954:Models, Biological; D032446:Myoblasts / Q000166:cytology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D018232:Rhabdomyosarcoma, Alveolar / Q000378:metabolism*; D054875:Ubiquitination
D051766:Early Growth Response Protein 1; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors