Repurposing a Cyclin-Dependent Kinase 1 (CDK1) Mitotic Regulatory Network to Complete Terminal Differentiation in Lens Fiber Cells.
Repurposing a Cyclin-Dependent Kinase 1 (CDK1) Mitotic Regulatory Network to Complete Terminal Differentiation in Lens Fiber Cells.
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DOI：
10.1167/iovs.64.2.6
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发表时间：
2023-02-01
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
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作者：
在透镜纤维细胞分化期间，细胞器以有序的方式被去除以确保透镜的清晰度。这个过程中的一个关键步骤是去除细胞核，但这一过程发生的机制尚不清楚。在这项研究中，我们调查的作用，细胞周期蛋白依赖性激酶1（CDK1）的调控环控制透镜纤维细胞去核（LFCD）。我们在两种不同的脊椎动物模型中对透镜分化进行了组织学检查。使用鸡胚透镜培养系统来测试CDK 1、细胞分裂周期25（CDC 25）、WEE 1和PP 2A在LFCD中的作用。此外，我们使用了三种表达高水平CDK抑制剂p27的小鼠模型来测试p27水平的增加是否会影响LFCD。使用鸡透镜器官培养物，CDK 1和CDC 25的小分子抑制剂抑制LFCD，而抑制CDK 1抑制性激酶WEE 1增强LFCD。此外，用间接抑制CDK1活性的PP2A抑制剂治疗也增加了LFCD。通过不同机制表达增加水平的p27的三种不同小鼠模型显示出受损的LFCD。在这里，我们定义了一个保守的非有丝分裂的作用，CDK1及其上游调控LFCD控制。我们发现，CDK1与WEE 1（一种抑制CDK1活性的核激酶）和CDC25激活磷酸酶在细胞中相互作用，其中CDK1活性必须受到精细调节以允许LFCD。我们还在多种体内模型中提供了遗传学证据，证明p27（一种CDK1抑制剂）抑制透镜生长和LFCD。
During lens fiber cell differentiation, organelles are removed in an ordered manner to ensure lens clarity. A critical step in this process is removal of the cell nucleus, but the mechanisms by which this occurs are unclear. In this study, we investigate the role of a cyclin-dependent kinase 1 (CDK1) regulatory loop in controlling lens fiber cell denucleation (LFCD). We examined lens differentiation histologically in two different vertebrate models. An embryonic chick lens culture system was used to test the role of CDK1, cell division cycle 25 (CDC25), WEE1, and PP2A in LFCD. Additionally, we used three mouse models that express high levels of the CDK inhibitor p27 to test whether increased p27 levels affect LFCD. Using chick lens organ cultures, small-molecule inhibitors of CDK1 and CDC25 inhibit LFCD, while inhibiting the CDK1 inhibitory kinase WEE1 potentiates LFCD. Additionally, treatment with an inhibitor of PP2A, which indirectly inhibits CDK1 activity, also increased LFCD. Three different mouse models that express increased levels of p27 through different mechanisms show impaired LFCD. Here we define a conserved nonmitotic role for CDK1 and its upstream regulators in controlling LFCD. We find that CDK1 functionally interacts with WEE1, a nuclear kinase that inhibits CDK1 activity, and CDC25 activating phosphatases in cells where CDK1 activity must be exquisitely regulated to allow for LFCD. We also provide genetic evidence in multiple in vivo models that p27, a CDK1 inhibitor, inhibits lens growth and LFCD.
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影响因子：
3.4
作者：
Brennan LA;McGreal-Estrada R;Logan CM;Cvekl A;Menko AS;Kantorow M
通讯作者：
Kantorow M
DOI：
10.1126/science.abk0410
发表时间：
2021-12-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gulluni F;Prever L;Li H;Krafcikova P;Corrado I;Lo WT;Margaria JP;Chen A;De Santis MC;Cnudde SJ;Fogerty J;Yuan A;Massarotti A;Sarijalo NT;Vadas O;Williams RL;Thelen M;Powell DR;Schueler M;Wiesener MS;Balla T;Baris HN;Tiosano D;McDermott BM Jr;Perkins BD;Ghigo A;Martini M;Haucke V;Boura E;Merlo GR;Buchner DA;Hirsch E
通讯作者：
Hirsch E
影响因子：
3.7
作者：
Caceres A;Shang F;Wawrousek E;Liu Q;Avidan O;Cvekl A;Yang Y;Haririnia A;Storaska A;Fushman D;Kuszak J;Dudek E;Smith D;Taylor A
通讯作者：
Taylor A
影响因子：
21.3
作者：
Carrano, AC;Eytan, E;Pagano, M
通讯作者：
Pagano, M
影响因子：
28.5
作者：
Ghelli Luserna di Rorà A;Cerchione C;Martinelli G;Simonetti G
通讯作者：
Simonetti G