PAX3-FOXO1 controls expression of the p57Kip2 cell-cycle regulator through degradation of EGR1.
The chimeric protein PAX3-FOXO1, resulting from a translocation between chromosomes 2 and 13, is the most common genetic aberration in the alveolar subtype of the human skeletal muscle tumor, rhabdomyosarcoma. To understand how PAX3-FOXO1 contributes to tumor development, we isolated and characterized muscle cells from transgenic mice expressing PAX3-FOXO1 under control of the PAX3 promoter. We demonstrate that these myoblasts are unable to complete myogenic differentiation because of an inability to up-regulate p57Kip2 transcription. This defect is caused by reduced levels of the EGR1 transcriptional activator resulting from a direct, destabilizing interaction with PAX3-FOXO1. Neither PAX3 nor FOXO1 share the ability to regulate p57Kip2 transcription. Thus, the breakage and fusion of the genes encoding these transcription factors creates a unique chimeric protein that controls a key cell-cycle and -differentiation regulator.
Roeb
Wendy
W
Ludwig Institute for Cancer Research, Biomedical Sciences Graduate Program, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0660, USA.
Boyer
Antonia
A
Cavenee
Webster K
WK
Arden
Karen C
KC
D000818:Animals; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008822:Mice, Transgenic; D019042:Muscle Neoplasms / Q000235:genetics; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012208:Rhabdomyosarcoma / Q000235:genetics
D050761:Cyclin-Dependent Kinase Inhibitor p57; C497325:EGR1 protein, human; 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