Amplification of MDM2 inhibits MyoD-mediated myogenesis.
One obvious phenotype of tumor cells is the lack of terminal differentiation. We previously classified rhabdomyosarcoma cell lines as having either a recessive or a dominant nondifferentiating phenotype. To study the genetic basis of the dominant nondifferentiating phenotype, we utilized microcell fusion to transfer chromosomes from rhabdomyosarcoma cells into C2C12 myoblasts. Transfer of a derivative chromosome 14 inhibits differentiation. The derivative chromosome 14 contains a DNA amplification. MDM2 is amplified and overexpressed in these nondifferentiating hybrids and in the parental rhabdomyosarcoma. Forced expression of MDM2 inhibits MyoD-dependent transcription. Expression of antisense MDM2 restores MyoD-dependent transcriptional activity. We conclude that amplification and overexpression of MDM2 inhibit MyoD function, resulting in a dominant nondifferentiating phenotype.
Fiddler
T A
TA
Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland 97201, USA.
Smith
L
L
Tapscott
S J
SJ
Thayer
M J
MJ
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002459:Cell Fusion; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D004843:Epistasis, Genetic; D005784:Gene Amplification; D005786:Gene Expression Regulation; D006801:Humans; D006822:Hybrid Cells / Q000473:pathology*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D009132:Muscles / Q000166:cytology*; D017570:MyoD Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D009124:Muscle Proteins; D017570:MyoD Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2