p53 tumor suppressor protein regulates the levels of huntingtin gene expression
p53 tumor suppressor protein regulates the levels of huntingtin gene expression
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DOI：
10.1038/sj.onc.1209021
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发表时间：
2006-01-01
期刊：
影响因子：
8
通讯作者：
Levine, AJ
中科院分区：
文献类型：
--
作者：
Feng, Z;Jin, S;Levine, AJ
p53蛋白是一种转录因子，它整合各种细胞应激信号。具有扩展的多聚谷氨酰胺束的突变亨廷顿蛋白的积累在人类亨廷顿病的病理过程中起核心作用。我们发现亨廷顿基因包含多个假定的p53反应元件，并且p53在体内和体外都与这些元件结合。在培养的人类细胞中，通过温度敏感型突变p53蛋白或γ射线照射激活p53，会增加亨廷顿mRNA和蛋白的表达。同样，鼠类亨廷顿蛋白也包含多个假定的p53反应元件，并且其在培养细胞中的表达可由p53激活诱导。此外，激活p53的γ射线照射可增加p53+/+小鼠（而非同基因的p53 -/-小鼠）大脑纹状体和皮质（亨廷顿病的主要病变部位）中亨廷顿基因的表达。这些结果表明p53蛋白可在转录水平调节亨廷顿蛋白的表达，并提示p53应激反应可能是亨廷顿病进程的一个调节因素。
The p53 protein is a transcription factor that integrates various cellular stress signals. The accumulation of the mutant huntingtin protein with an expanded polyglutamine tract plays a central role in the pathology of human Huntington's disease. We found that the huntingtin gene contains multiple putative p53-responsive elements and p53 binds to these elements both in vivo and in vitro. p53 activation in cultured human cells, either by a temperature-sensitive mutant p53 protein or by gamma-irradiation (gamma-irradiation), increases huntingtin mRNA and protein expression. Similarly, murine huntingtin also contains multiple putative p53-responsive elements and its expression is induced by p53 activation in cultured cells. Moreover, gamma-irradiation, which activates p53, increases huntingtin gene expression in the striatum and cortex of mouse brain, the major pathological sites for Huntington's disease, in p53+/+ but not the isogenic p53 -/- mice. These results demonstrate that p53 protein can regulate huntingtin expression at transcriptional level, and suggest that a p53 stress response could be a modulator of the process of Huntington's disease.