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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: Phenotypes reversed by a tumorigenic mutation
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G1 cell cycle arrest and apoptosis induction by nuclear Smad4/Dpc4: Phenotypes reversed by a tumorigenic mutation

机译：G1细胞周期停滞和核Smad4 / Dpc4诱导的细胞凋亡：致瘤突变逆转的表型

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摘要

The tumor suppressor Smad4/DPc4 is a transcription activator that binds specific DNA sequences and whose nuclear localization is induced after exposure to type beta transforming growth factor-like cytokines. We explored an inducible system in which Smad4 protein is activated by translocation to the nucleus when cell lines that stably cxpress wild-type or mutant Smad4 proteins fused to a murine estrogen receptor domain are treated with 4-hydroxytamox- ifen. This induced Smad4-mediated tran scriptional activation and a decrease in growth rate, attributable to a cell cycle arrest at the G1 phase and an induction of apoptosis. A lumor-derived mutation affecting a residue critical for DNA-binding demonstrated an ``oncogenic'' phe- notype, having decreases in both the G1 fraction and apoptosis and, consequently, an augmentation of population growth. This model should be useful in the exploration and control of components that lie further downstream in the Smad4 tumor- suppressor pathway.
机译：肿瘤抑制物Smad4 / DPc4是一种转录激活剂，结合特定的DNA序列，其核定位是在暴露于β型转化生长因子样细胞因子后诱导的。我们探索了一种可诱导系统，其中当用4-羟基他莫昔芬处理稳定地将野生型或突变型Smad4蛋白融合到鼠雌激素受体域的细胞系时，通过转运到细胞核来激活Smad4蛋白。这诱导了Smad4介导的转录激活和生长速率的降低，这归因于G1期的细胞周期停滞和细胞凋亡的诱导。鲁棒性突变影响了对DNA结合至关重要的残基，表现出``致癌''表型，G1分数和细胞凋亡均降低，因此种群增长增加。该模型在探索和控制位于Smad4肿瘤抑制途径中更下游的成分时应该是有用的。

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