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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation
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FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation

机译：FOXO3a依赖Pink1（Park6）的调节介导细胞因子剥夺的生存信号。

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摘要

Loss-of-function mutations of phosphatase/tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (Pink1) (also known as Park6) identified in familial forms of Parkinson's disease (PD) are associated with compromised mitochondrial function. Emerging data suggest that Pink1 is an essential pro-survival factor that is induced in response to oxidative stress. However, the mechanisms regulating Pink1 expression under stress conditions remain unknown. Forkhead box, subgroup O (FOXO) transcription factors carry out distinct biological functions in response to different extracellular signals. Notably, FOXO factors possess evolutionary conserved roles in protecting cells from oxidative stress-induced death. Here we report that the FOXO family member FOXO3a controls Pink1 transcription in both mouse and human cells subjected to growth factor deprivation and that this regulation is exerted through evolu-tionarily conserved FOXO binding elements. Induction of Pink1 by FOXO3a is crucial for survival signals in lymphocytes, as depletion of Pink1 sensitizes these cells to death induced by deprivation of an essential growth factor. Our data reveal that the role of FOXO factors in protecting cells from growth factor deprivation-triggered apopto-sis has been underestimated and that FOXOs mediate this protection by transactivating anti-apoptotic effectors like Pink1. Given the essential role of Pink1 in combating cell death, our findings may help to dissect the mechanisms by which FOXO proteins function as anti-oxidative stress factors.
机译：在帕金森氏病（PD）家族型中鉴定出的10号染色体（PTEN）诱导的假定激酶1（Pink1）（也称为Park6）缺失的磷酸酶/张力蛋白同源物的功能丧失突变与线粒体功能受损有关。新兴数据表明，Pink1是一种重要的生存因子，可以响应氧化应激而被诱导。但是，在压力条件下调节Pink1表达的机制仍然未知。叉头盒O亚型（FOXO）转录因子响应不同的细胞外信号执行不同的生物学功能。值得注意的是，FOXO因子在保护细胞免受氧化应激诱导的死亡中具有进化上的保守作用。在这里我们报告说，FOXO家族成员FOXO3a控制老鼠和人类细胞中受到生长因子剥夺的Pink1转录，并且这种调控是通过进化上保守的FOXO结合元件来实现的。 FOXO3a对Pink1的诱导对于淋巴细胞中的存活信号至关重要，因为Pink1的耗尽会使这些细胞对由必需生长因子的缺乏引起的死亡敏感。我们的数据表明，FOXO因子在保护细胞免受生长因子剥夺触发的细胞凋亡的作用中被低估了，并且FOXO通过反激活像Pink1这样的抗凋亡效应子来介导这种保护作用。鉴于Pink1在对抗细胞死亡中的重要作用，我们的发现可能有助于剖析FOXO蛋白作为抗氧化应激因子的机制。

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    Yang Mei; Yiru Zhang; Kazuo Yamamoto; Wei Xie; Tak W. Mak; Han You;

  • 作者单位

    Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, 422 South Siming Road, Xiamen, Fujian 361005, China;

    Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, 422 South Siming Road, Xiamen, Fujian 361005, China;

    The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, ON, Canada M5G 2C1;

    Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, 422 South Siming Road, Xiamen, Fujian 361005, China;

    The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, ON, Canada M5G 2C1;

    Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, 422 South Siming Road, Xiamen, Fujian 361005, China;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    apoptosis; oxidative stress; transcription;

    机译：细胞凋亡氧化应激抄写;

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