Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect
Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect
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DOI：
10.1073/pnas.1113884108
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发表时间：
2011-09-27
影响因子：
11.1
通讯作者：
Feng, Zhaohui
中科院分区：
文献类型：
--
作者：
Zhang, Cen;Lin, Meihua;Feng, Zhaohui
调节能量代谢是p53在肿瘤抑制中的一种新功能。Parkin（PARK 2）是一个帕金森病相关基因，是一种潜在的肿瘤抑制基因，其表达在肿瘤中经常减少。在这里，Parkin被鉴定为p53靶基因，其是p53在调节能量代谢中的功能的重要介质。人类和小鼠帕金基因含有功能性p53应答元件，并且p53增加人类和小鼠中帕金的转录。帕金蛋白参与p53在葡萄糖代谢中的功能;帕金蛋白缺乏激活糖酵解并减少线粒体呼吸，导致瓦尔堡效应。Parkin表达的恢复逆转了细胞中的瓦尔堡效应。因此，帕金缺陷是肿瘤中瓦尔堡效应的一种新机制。帕金蛋白还有助于p53在抗氧化防御中的功能。此外，帕金缺乏症使小鼠对γ辐射诱导的肿瘤发生敏感，这提供了进一步的直接证据来支持帕金在肿瘤抑制中的作用。我们的研究结果表明，作为一个新的组成部分，在p53通路，帕金有助于p53的功能，在调节能量代谢，特别是瓦尔堡效应，和抗氧化防御，从而在肿瘤抑制p53的功能。
Regulation of energy metabolism is a novel function of p53 in tumor suppression. Parkin (PARK2), a Parkinson disease-associated gene, is a potential tumor suppressor whose expression is frequently diminished in tumors. Here Parkin was identified as a p53 target gene that is an important mediator of p53's function in regulating energy metabolism. The human and mouse Parkin genes contain functional p53 responsive elements, and p53 increases the transcription of Parkin in both humans and mice. Parkin contributes to the function of p53 in glucose metabolism; Parkin deficiency activates glycolysis and reduces mitochondrial respiration, leading to the Warburg effect. Restoration of Parkin expression reverses the Warburg effect in cells. Thus, Parkin deficiency is a novel mechanism for the Warburg effect in tumors. Parkin also contributes to the function of p53 in antioxidant defense. Furthermore, Parkin deficiency sensitizes mice to gamma-irradiation-induced tumorigenesis, which provides further direct evidence to support a role of Parkin in tumor suppression. Our results suggest that as a novel component in the p53 pathway, Parkin contributes to the functions of p53 in regulating energy metabolism, especially the Warburg effect, and antioxidant defense, and thus the function of p53 in tumor suppression.