Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors
Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors
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DOI：
10.1006/mcne.2001.1000
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发表时间：
2001-07-01
影响因子：
3.5
通讯作者：
Stamm, S
中科院分区：
文献类型：
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作者：
Hartmann, AM;Rujescu, D;Stamm, S
Tau是一种微管相关蛋白，其转录物在哺乳动物神经系统中经历受调节的剪接。该基因的外显子10是一个选择性剪接盒，是成人特异性的，编码微管结合结构域。增加包含外显子10的突变导致产生主要含有四个微管结合重复序列的tau蛋白，并显示引起与染色体17（FTDP-17）相关的额颞叶痴呆和帕金森综合征。在这里，我们表明，外显子10的使用是由CDC 2样激酶CLK 1，2，3和4，磷酸化丝氨酸精氨酸丰富的蛋白质，这反过来又调节前mRNA剪接。共转染实验表明，CLKs通过从核储存位点释放特异性蛋白质来实现这种效果。我们的研究结果表明，通过磷酸化改变前mRNA加工途径可能是tau蛋白病的一个新的治疗概念。
Tau is a microtubule-associated protein whose transcript undergoes regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and encodes a microtubule-binding domain. Mutations increasing the inclusion of exon 10 result in the production of tau protein which predominantly contains four microtubule-binding repeats and were shown to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Here we show that exon 10 usage is regulated by CDC2-like kinases CLK1, 2, 3, and 4 that phosphorylate serine-arginine-rich proteins, which in turn regulate pre-mRNA splicing. Cotransfection experiments suggest that CLKs achieve this effect by releasing specific proteins from nuclear storage sites. Our results show that changing pre-mRNA-processing pathways through phosphorylation could be a new therapeutic concept for tauopathies.