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神内清木虫 (著名写手)
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Two genes on chromosome 21, namely dual specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) and regulator of calcineurin 1 (RCAN1), have been implicated in some of the phenotypic characteristics of Down syndrome, including the early onset of Alzheimer disease. Although a link between Dyrk1A and RCAN1 and the nuclear factor of activated T cells (NFAT) pathway has been reported, it remains unclear whether Dyrk1A directly interacts with RCAN1. In the present study, Dyrk1A is shown to directly interact with and phosphorylate RCAN1 at Ser(112) and Thr(192) residues。Dyrk1A-mediated phosphorylation of RCAN1 at Ser(112) primes the protein for the GSK3beta-mediated phosphorylation of Ser(108). Phosphorylation of RCAN1 at Thr(192) by Dyrk1A enhances the ability of RCAN1 to inhibit the phosphatase activity of calcineurin (Caln), leading to reduced NFAT transcriptional activity and enhanced Tau phosphorylation. These effects are mediated by the enhanced binding of RCAN1 to Caln and its extended half-life caused by Dyrk1A-mediated phosphorylation. Furthermore, an increased expression of phospho-Thr(192)-RCAN1 was observed in the brains of transgenic mice overexpressing the Dyrk1A protein. These results suggest a direct link between Dyrk1A and RCAN1 in the Caln-NFAT signaling and Tau hyperphosphorylation pathways, supporting the notion that the synergistic interaction between the chromosome 21 genes RCAN1 and Dyrk1A is associated with a variety of pathological features associated with DS。只翻译红色内容 [ Last edited by 神内清 on 2013-1-20 at 19:29 ] |
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zhtear99
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神内清: 金币+25, ★★★很有帮助, 不错，挺专业的，个别小地方的错误！可见英语水平确实很高！ 2013-01-21 16:00:57
感谢参与，应助指数 +1
神内清: 金币+25, ★★★很有帮助, 不错，挺专业的，个别小地方的错误！可见英语水平确实很高！ 2013-01-21 16:00:57
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双特异性酪氨酸磷酸化调节激酶1A(Dyrk1A)介导钙调磷酸酶调节蛋白1(RCAN1)Ser112位点的磷酸化引发了糖原合酶激酶-3β(GSK3beta)介导的蛋白Ser108位点的磷酸化。RCAN1上的Thr192位点经RCAN1磷酸化后，可增强RCAN1抑制钙调磷酸酶的磷酸酶活性，导致T细胞活化核因子(NFAT)转录活性的降低和Tau磷酸化的增强。此外，在过量表达Dyrk1A的转基因小鼠的脑中观测到磷酸化-Thr192-RCAN1表达量的增加。这些结果暗示了在Caln-NFAT信号通路和Tau高度磷酸化通路中Dyrk1A 和 RCAN1有直接的联系，支持了21号染色体上Dyrk1A 和 RCAN1基因间具有协同作用的观点，而该作用与唐氏综合症(DS)相关的许多病理特征是有关的。 [ Last edited by zhtear99 on 2013-1-21 at 10:17 ] |
2楼2013-01-21 09:50:00
