REST Regulates DYRK1A Transcription in a Negative Feedback Loop
REST Regulates DYRK1A Transcription in a Negative Feedback Loop
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DOI：
10.1074/jbc.m110.174540
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发表时间：
2011-03-25
影响因子：
4.8
通讯作者：
Sun, Xiulian
中科院分区：
文献类型：
--
作者：
Lu, Mei;Zheng, Lanlan;Sun, Xiulian
DYRK 1A（双特异性酪氨酸磷酸化调节激酶1A）已被证明参与阿尔茨海默病和唐氏综合征的学习和记忆障碍。DYRK 1A作为果蝇小脑基因的同源基因，在神经发育中也发挥重要作用，但DYRK 1A在神经发育中的功能及其调控机制尚不清楚。REST（RE 1 silencing transcription factor，RE 1沉默转录因子）在神经元分化中起重要作用。在此，我们发现REST可以通过位于人DYRK 1A启动子-833至-815 bp处的神经元限制性沉默元件激活DYRK 1A的转录。DYRK 1A和REST在小鼠脑中的协调表达进一步支持了DYRK 1A和REST在神经发育过程中的交叉相互作用。此外，我们发现DYRK 1A剂量失衡通过促进REST蛋白的泛素化和随后的降解降低REST蛋白的稳定性和转录活性。因此，DYRK 1A在负反馈回路中通过REST调节，表明DYRK 1A和REST在神经发育中密切相关。
DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) has been shown to be involved in learning and memory impairments in Alzheimer disease and Down syndrome. As a homolog of Drosophila minibrain gene, DYRK1A also plays important roles in neurodevelopment; however, the function and regulatory mechanism of DYRK1A in neurodevelopment remain elusive. REST (RE1 silencing transcription factor) plays vital roles in neuronal differentiation. Here, we found that REST can activate DYRK1A transcription via a neuron-restrictive silencer element at bp -833 to -815 of human DYRK1A promoter. The coordinated expression of DYRK1A and REST in mouse brain further supports the cross-interaction of DYRK1A and REST during neurodevelopment. Moreover, we showed that DYRK1A dosage imbalance reduced REST protein stability and transcriptional activity through facilitating ubiquitination and subsequent degradation of REST protein. Therefore, the regulation of DYRK1A by REST in a negative feedback loop suggests that DYRK1A and REST are closely related in neurodevelopment.