Defects in transforming growth factor-β signaling cooperate with a Ras oncogene to cause vapid aneuploidy and malignant transformation of mouse keratinocytes
Defects in transforming growth factor-β signaling cooperate with a Ras oncogene to cause vapid aneuploidy and malignant transformation of mouse keratinocytes
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DOI：
10.1073/pnas.96.26.14949
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发表时间：
1999-12-21
影响因子：
11.1
通讯作者：
Yuspa, SH
中科院分区：
文献类型：
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作者：
Glick, A;Popescu, N;Yuspa, SH
转化生长因子-β（TGF-β）信号通路的遗传失活可加速多阶段癌变小鼠表皮模型中的肿瘤进展。通过使用与体内恶性转化为鳞状细胞癌平行的角质形成细胞转化的体外模型，我们表明v-ras（Ha）转导的原代TGF-β 1-/-角质形成细胞和表达TGF-β II型显性负性受体转基因的角质形成细胞比对照基因型具有显著更高的自发转化频率，TGF-β 1-/-角质形成细胞的恶性转化之前是染色体畸变的非整倍性和累积。类似地，用II型显性负性受体腺病毒瞬时失活TGF-β信号传导导致倍性的快速变化。外源性TGF-β 1可以在不显著阻止细胞增殖的浓度下抑制TGF-β 1-/-角质形成细胞的非整倍性、染色体断裂和恶性转化。这些结果表明，基因组不稳定性是一种机制，通过这种机制，TGF-β信号传导的缺陷可以加速小鼠多阶段癌变过程中的肿瘤进展。
Genetic inactivation of the transforming growth factor-beta (TGF-beta) signaling pathway can accelerate tumor progression in the mouse epidermal model of multistage carcinogenesis. By using an in vitro model of keratinocyte transformation that parallels in vivo malignant conversion to squamous cell carcinoma, we show that v-ras(Ha) transduced primary TGF-beta 1-/- keratinocytes and keratinocytes expressing a TGF-beta type II dominant-negative receptor transgene have significantly higher frequencies of spontaneous transformation than control genotypes, Malignant transformation in the TGF-beta 1-/- keratinocytes is preceded by aneuploidy and accumulation of chromosomal aberrations. Similarly, transient inactivation of TGF-beta signaling with a type II dominant-negative receptor adenovirus causes rapid changes in ploidy, Exogenous TGF-beta 1 can suppress aneuploidy, chromosome breaks, and malignant transformation of the TGF-beta 1-/- keratinocytes at concentrations that do not significantly arrest cell proliferation. These results point to genomic instability as a mechanism by which defects in TGF-beta signaling could accelerate tumor progression in mouse multistage carcinogenesis.