Fiddler T A, Smith L, Tapscott S J, Thayer M J
Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland 97201, USA.
Mol Cell Biol. 1996 Sep;16(9):5048-57. doi: 10.1128/MCB.16.9.5048.
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.
肿瘤细胞的一个明显表型是缺乏终末分化。我们之前将横纹肌肉瘤细胞系分类为具有隐性或显性未分化表型。为了研究显性未分化表型的遗传基础，我们利用微细胞融合技术将横纹肌肉瘤细胞的染色体转移到C2C12成肌细胞中。14号衍生染色体的转移会抑制分化。14号衍生染色体包含一个DNA扩增区域。MDM2在这些未分化的杂种细胞和横纹肌肉瘤亲本细胞中均发生扩增并过表达。MDM2的强制表达会抑制MyoD依赖的转录。反义MDM2的表达可恢复MyoD依赖的转录活性。我们得出结论，MDM2的扩增和过表达会抑制MyoD功能，从而导致显性未分化表型。
