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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Defective cardiovascular development and elevated cyclin E and notch proteins in mice lacking the Fbw7 F-box protein
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Defective cardiovascular development and elevated cyclin E and notch proteins in mice lacking the Fbw7 F-box protein

机译：缺乏Fbw7 F-box蛋白的小鼠的心血管发育不良和细胞周期蛋白E和Notch蛋白升高

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摘要

The mammalian F-box protein Fbw7 and its Caenorhabditis elegans counterpart Sel-10 have been implicated in the ubiquitin-mediated turnover of cyclin E as well as the Notch/Lin-12 family of transcriptional activators. Both unregulated Notch and cyclin E promote tumorigenesis, and inactivating mutations in human Fbw7 suggest that it may be a tumor suppressor. To generate an in vivo system to assess the consequences of such unregulated signaling, we generated mice deficient for Fbw7. Fbw7-null mice die around 10.5 days post coitus because of a combination of deficiencies in hematopoietic and vascular development and heart chamber maturation. The absence of Fbw7 results in elevated levels of cyclin E, concurrent with inappropriate DNA replication in placental giant trophoblast cells. Moreover, the levels of both Notch 1 and Notch 4 intracellular domains were elevated, leading to stimulation of downstream transcriptional pathways involving Hes1, Herp1, and Herp2. These data suggest essential functions for Fbw7 in controlling cyclin E and Notch signaling pathways in the mouse. [References: 74]
机译：哺乳动物F-box蛋白Fbw7及其秀丽隐杆线虫对应的Sel-10与遍在蛋白介导的细胞周期蛋白E以及Notch / Lin-12家族的转录激活因子的更新有关。 Notch和cyclin E不受控制都促进肿瘤发生，而人类Fbw7的失活突变表明它可能是肿瘤抑制因子。为了生成一个体内系统来评估这种不受调节的信号转导的后果，我们生成了缺乏Fbw7的小鼠。 Fbw7-null小鼠在性交后约10.5天死亡，因为造血和血管发育以及心腔成熟的缺陷。 Fbw7的缺乏会导致细胞周期蛋白E水平升高，并在胎盘巨大滋养层细胞中复制不当的DNA。此外，Notch 1和Notch 4细胞内结构域的水平均升高，导致刺激涉及Hes1，Herp1和Herp2的下游转录途径。这些数据表明Fbw7在控制细胞周期蛋白E和Notch信号通路中的基本功能。 [参考：74]

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