期刊
NATURE CELL BIOLOGY
卷 10, 期 6, 页码 643-653出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1727
关键词
-
类别
资金
- Howard Hughes Medical Institute Funding Source: Medline
- Medical Research Council [MC_U117570528] Funding Source: Medline
- NIGMS NIH HHS [R01 GM057587, R01 GM057587-11] Funding Source: Medline
- MRC [MC_U117570528] Funding Source: UKRI
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM057587] Funding Source: NIH RePORTER
Development of the nervous system requires that timely withdrawal from the cell cycle be coupled with initiation of differentiation. Ubiquitin-mediated degradation of the N-Myc oncoprotein in neural stem/ progenitor cells is thought to trigger the arrest of proliferation and begin differentiation. Here we report that the HECT-domain ubiquitin ligase Huwe1 ubiquitinates the N-Myc oncoprotein through Lys 48-mediated linkages and targets it for destruction by the proteasome. This process is physiologically implemented by embryonic stem (ES) cells differentiating along the neuronal lineage and in the mouse brain during development. Genetic and RNA interference-mediated inactivation of the Huwe1 gene impedes N-Myc degradation, prevents exit from the cell cycle by opposing the expression of Cdk inhibitors and blocks differentiation through persistent inhibition of early and late markers of neuronal differentiation. Silencing of N-myc in cells lacking Huwe1 restores neural differentiation of ES cells and rescues cell-cycle exit and differentiation of the mouse cortex, demonstrating that Huwe1 restrains proliferation and enables neuronal differentiation by mediating the degradation of N-Myc. These findings indicate that Huwe1 links destruction of N-Myc to the quiescent state that complements differentiation in the neural tissue.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据