P44, the 'longevity-assurance' isoform of P53, regulates tau phosphorylation and is activated in an age-dependent fashion.
P44, the 'longevity-assurance' isoform of P53, regulates tau phosphorylation and is activated in an age-dependent fashion.
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DOI：
10.1111/acel.12192
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发表时间：
2014-06
期刊：
影响因子：
7.8
通讯作者：
Puglielli L
中科院分区：
文献类型：
--
作者：
Pehar M;Ko MH;Li M;Scrable H;Puglielli L
p44是p53的短同种型，具有“长寿保证”活性。p44在小鼠（p44+/+转基因小鼠）中的过表达导致模拟加速老化形式的早衰样表型。表型包括微管结合蛋白tau的异常磷酸化、突触缺陷和认知能力下降。基因工程表明，tau蛋白的磷酸化状态在突触缺陷的上游起作用。在这里，我们提供的证据表明，p44促进磷酸化的tau蛋白在小鼠。具体来说，我们发现p44与tau激酶Dyrk 1A、GSK 3 β、Cdk 5、p35和p39的启动子结合，并激活它们的转录。上述激酶的上调之后是tau的磷酸化增加。最后，我们发现，p44是优先发现在细胞核中，其水平随着年龄的增长，在小鼠大脑。总之，这些结果表明，p53：p44比例的不平衡可能与衰老特征的tau代谢改变有关。
p44 is a short isoform of p53 with ‘longevity-assurance’ activity. Overexpression of p44 in the mouse (p44+/+ transgenic mice) causes a progeroid phenotype that mimics an accelerated form of aging. The phenotype includes abnormal phosphorylation of the microtubule-binding protein tau, synaptic deficits, and cognitive decline. Genetic engineering demonstrated that the phosphorylation status of tau acts upstream of the synaptic deficits. Here, we provide evidence that p44 promotes the phosphorylation of tau in the mouse. Specifically, we show that p44 binds to the promoter of tau kinases Dyrk1A, GSK3β, Cdk5, p35, and p39 and activates their transcription. The upregulation of the above kinases is followed by increased phosphorylation of tau. Finally, we show that p44 is preferentially found in the nucleus and that its levels increase with age in the mouse brain. Taken together, these results suggest that an imbalance in the p53:p44 ratio might be involved with the altered tau metabolism that characterizes aging.
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