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首页> 外文期刊>Cell cycle >The down syndrome-related protein kinase DYRK1A phosphorylates p27 Kip1and cyclin D1 and induces cell cycle exit and neuronal differentiation
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The down syndrome-related protein kinase DYRK1A phosphorylates p27 Kip1and cyclin D1 and induces cell cycle exit and neuronal differentiation

机译：唐氏综合症相关蛋白激酶DYRK1A磷酸化p27 Kip1和细胞周期蛋白D1，并诱导细胞周期退出和神经元分化

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摘要

A fundamental question in neurobiology is how the balance between proliferation and differentiation of neuronal precursors is maintained to ensure that the proper number of brain neurons is generated. Substantial evidence implicates DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) as a candidate gene responsible for altered neuronal development and brain abnormalities in Down syndrome. Recent findings support the hypothesis that DYRK1A is involved in cell cycle control. Nonetheless, how DYRK1A contributes to neuronal cell cycle regulation and thereby affects neurogenesis remains poorly understood. In the present study we have investigated the mechanisms by which DYRK1A affects cell cycle regulation and neuronal differentiation in a human cell model, mouse neurons, and mouse brain. Dependent on its kinase activity and correlated with the dosage of overexpression, DYRK1A blocked proliferation of SH-SY5Y neuroblastoma cells within 24 h and arrested the cells in G1 phase. Sustained overexpression of DYRK1A induced G0 cell cycle exit and neuronal differentiation. Furthermore, we provide evidence that DYRK1A modulated protein stability of cell cycle-regulatory proteins. DYRK1A reduced cellular Cyclin D1 levels by phosphorylation on Thr286, which is known to induce proteasomal degradation. In addition, DYRK1A phosphorylated p27Kip1 on Ser10, resulting in protein stabilization. Inhibition of DYRK1A kinase activity reduced p27Kip1 Ser10 phosphorylation in cultured hippocampal neurons and in embryonic mouse brain. In aggregate, these results suggest a novel mechanism by which overexpression of DYRK1A may promote premature neuronal differentiation and contribute to altered brain development in Down syndrome.
机译：神经生物学中的一个基本问题是如何保持神经元前体细胞的增殖与分化之间的平衡，以确保产生适当数量的大脑神经元。大量证据表明，DYRK1A（双重特异性酪氨酸磷酸化调节激酶1A）是唐氏综合症中负责神经元发育和脑异常改变的候选基因。最近的发现支持DYRK1A参与细胞周期控制的假说。尽管如此，关于DYRK1A如何促进神经元细胞周期调节并进而影响神经发生的认识仍知之甚少。在本研究中，我们已经研究了DYRK1A影响人细胞模型，小鼠神经元和小鼠脑中细胞周期调控和神经元分化的机制。取决于其激酶活性并与过量表达的剂量相关，DYRK1A在24小时内阻断SH-SY5Y神经母细胞瘤细胞的增殖并将其阻滞在G1期。 DYRK1A持续过度表达诱导G0细胞周期退出和神经元分化。此外，我们提供了DYRK1A调节细胞周期调控蛋白的蛋白质稳定性的证据。 DYRK1A通过在Thr286上进行磷酸化来降低细胞周期蛋白D1的水平，已知该蛋白可诱导蛋白酶体降解。此外，DYRK1A使Ser10上的p27Kip1磷酸化，从而使蛋白质稳定。 DYRK1A激酶活性的抑制降低了培养的海马神经元和胚胎小鼠脑中的p27Kip1 Ser10磷酸化。总体而言，这些结果表明，DYRK1A的过表达可能促进唐氏综合症中神经元的过早分化并促进大脑发育的改变。

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