Defective cardiovascular development and elevated cyclin E and notch proteins in mice lacking the Fbw7 F-box protein
Defective cardiovascular development and elevated cyclin E and notch proteins in mice lacking the Fbw7 F-box protein
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DOI：
10.1073/pnas.0307875101
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发表时间：
2004-03-09
影响因子：
11.1
通讯作者：
Elledge, SJ
中科院分区：
文献类型：
--
作者：
Tetzlaff, MT;Yu, W;Elledge, SJ
哺乳动物F-box蛋白Fbw7及其秀丽隐杆线虫对应的Sel-10与泛素介导的细胞周期蛋白E和Notch/Lin-12转录激活因子家族的周转有关。不受调控的Notch和cyclin E都促进肿瘤的发生，人类Fbw7的失活突变表明它可能是一种肿瘤抑制因子。为了产生一个体内系统来评估这种不受调节的信号的后果，我们产生了Fbw7缺陷的小鼠。fbw7缺失的小鼠在交媾后10.5天左右死亡，原因是造血和血管发育以及心腔成熟的缺陷。Fbw7缺失导致细胞周期蛋白E水平升高，同时胎盘巨滋养细胞中DNA复制不适当。此外，细胞内Notch 1和Notch 4结构域的水平升高，导致下游包括Hes1、Herp1和Herp2的转录途径受到刺激。这些数据表明Fbw7在控制小鼠周期蛋白E和Notch信号通路中具有重要功能。
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.