Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells
Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells
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DOI：
10.1074/jbc.m110.147520
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发表时间：
2010-10-08
影响因子：
4.8
通讯作者：
Chung, Kwang Chul
中科院分区：
文献类型：
--
作者：
Park, Joongkyu;Oh, Yohan;Chung, Kwang Chul
唐氏综合征（Down syndrome，DS）与许多神经缺陷相关，包括脑体积缩小和神经元增殖受损，是导致智力低下的重要原因。DS的这些典型特征与人类21号染色体上的一个特定基因组“唐氏综合症关键区”（DSCR）密切相关。在这里，我们研究了受损的神经元增殖在DS的分子机制，更具体地说，双特异性酪氨酸-（Y）磷酸化调节激酶1A（Dyrk 1A），DSCR基因产物，在胚胎神经元细胞增殖的调节作用。我们发现，Dyrk 1A磷酸化p53在Ser-15在体外和永生化大鼠胚胎海马祖细胞H19-7细胞。此外，Dyrk 1A诱导的p53在Ser-15的磷酸化导致p53靶基因的强烈诱导（例如，G. p21（CIP 1））和受损的G（1）/G（0）-S相变，导致H19-7细胞和人胚胎干细胞衍生的神经前体细胞的增殖减弱。此外，p53-Ser-15点突变为丙氨酸挽救了Dyrk 1A对神经元增殖的抑制作用。因此，胚胎DYRK 1A转基因小鼠的大脑表现出Dyrk 1A、Ser-15（小鼠Ser-18）磷酸化p53和p21（CIP 1）水平升高以及神经元增殖受损。这些研究结果表明，上调Dyrk 1A有助于改变神经元增殖DS通过特定的磷酸化p53在Ser-15和随后的p21（CIP 1）诱导。
Down syndrome (DS) is associated with many neural defects, including reduced brain size and impaired neuronal proliferation, highly contributing to the mental retardation. Those typical characteristics of DS are closely associated with a specific gene group "Down syndrome critical region" (DSCR) on human chromosome 21. Here we investigated the molecular mechanisms underlying impaired neuronal proliferation in DS and, more specifically, a regulatory role for dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A), a DSCR gene product, in embryonic neuronal cell proliferation. We found that Dyrk1A phosphorylates p53 at Ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor H19-7 cells. In addition, Dyrk1A-induced p53 phosphorylation at Ser-15 led to a robust induction of p53 target genes (e. g. p21(CIP1)) and impaired G(1)/G(0)-S phase transition, resulting in attenuated proliferation of H19-7 cells and human embryonic stem cell-derived neural precursor cells. Moreover, the point mutation of p53-Ser-15 to alanine rescued the inhibitory effect of Dyrk1A on neuronal proliferation. Accordingly, brains from embryonic DYRK1A transgenic mice exhibited elevated levels of Dyrk1A, Ser-15 (mouse Ser-18)-phosphorylated p53, and p21(CIP1) as well as impaired neuronal proliferation. These findings suggest that up-regulation of Dyrk1A contributes to altered neuronal proliferation in DS through specific phosphorylation of p53 at Ser-15 and subsequent p21(CIP1) induction.