The anaphase-promoting complex coordinates initiation of lens differentiation
The anaphase-promoting complex coordinates initiation of lens differentiation
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DOI：
10.1091/mbc.e06-09-0809
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发表时间：
2007-03-01
影响因子：
3.3
通讯作者：
Wan, Yong
中科院分区：
文献类型：
--
作者：
Wu, George;Glickstein, Sara;Wan, Yong
晶状体的发育需要细胞分裂和分化的精确协调。细胞周期阻滞后分化程序启动的机制尚不清楚。细胞周期蛋白依赖性激酶抑制剂（CKIs），如p15和p21，已被认为是抑制G1进展的关键成分，因此，它们的激活对于静止是必要的，对于分化的开始很重要。p15和p21的调控主要受转化生长因子- β信号通路的调控。我们已经发现，Cdh1/APC是一种关键的泛素蛋白连接酶，通过促进tgf - β诱导的SnoN降解，在调节晶状体分化中发挥重要作用。SnoN是一种转录辅抑制因子，p15和p21的转录激活需要去除。RNA干扰导致的Cdh1缺失会减弱tgf - β介导的p15和p21的诱导，并显著阻断晶状体分化。不可降解SnoN的表达也显著减弱了晶状体诱导。此外，我们已经证明Cdh1和SnoN在晶状体分化开始时形成复合体。体内组织分析证实了我们的生化和遗传结果。因此，Cdh1/APC通过介导tgf - β信号诱导的SnoN破坏，对细胞周期进程的协调和晶状体分化的启动至关重要。
Lens development requires the precise coordination of cell division and differentiation. The mechanisms by which the differentiation program is initiated after cell cycle arrest remains not well understood. Cyclin-dependent kinase inhibitors (CKIs), such as p15 and p21, have been suggested to be critical components that inhibit G1 progression and therefore, their activation is necessary for quiescence and important for the onset of differentiation. Regulation of p15 and p21 is principally governed by transforming growth factor (TGF)-beta-signaling pathway. We have identified that Cdh1/APC, a critical ubiquitin protein ligase, plays an important role in regulating lens differentiation by facilitating TGF-beta-induced degradation of SnoN, a transcriptional corepressor that needs to be removed for transcriptional activation of p15 and p21. The depletion of Cdh1 by RNA interference attenuates the TGF-beta-mediated induction of p15 and p21 and significantly blocks lens differentiation. Expression of nondegradable SnoN also noticeably attenuates lens induction. Furthermore, we have shown that Cdh1 and SnoN form a complex at the onset of lens differentiation. In vivo histological analysis confirms our biochemical and genetic results. Thus, Cdh1/APC is crucial to the coordination of cell cycle progression and the initiation of lens differentiation through mediating TGF-beta-signaling-induced destruction of SnoN.