Rhabdomyosarcoma development in mice lacking Trp53 and Fos: tumor suppression by the Fos protooncogene.
The Fos protein, a major component of the AP-1 transcription factor, is essential for osteoclast differentiation, acts as an oncogene, potentiates transforming signals, and controls invasive growth and angiogenesis during tumor progression. To investigate a potential genetic interaction between the Trp53 and Fos pathways, Trp53/Fos double knockout mice were generated. These mice develop highly proliferative and invasive rhabdomyosarcomas of the facial and orbital regions, with more than 90% penetrance at 6 months of age. Rhabdomyosarcoma cell lines established from the primary tumors express characteristic muscle-specific markers, and reexpression of Fos is associated with enhanced apoptosis in vitro. Moreover, Fos is able to repress Pax7 expression in rhabdomyosarcoma cell lines and primary myoblasts, suggesting a molecular link to genetic alterations involved in human rhabdomyosarcomas.
Fleischmann
Alexander
A
Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Jochum
Wolfram
W
Eferl
Robert
R
Witowsky
James
J
Wagner
Erwin F
EF
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009154:Mutation; D010010:Osteoclasts / Q000378:metabolism*; D051763:PAX7 Transcription Factor; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018398:Homeodomain Proteins; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; C497322:Pax7 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1