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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dj-1/park7 Is An Important Mediator Of Hypoxia-induced Cellular Responses
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Dj-1/park7 Is An Important Mediator Of Hypoxia-induced Cellular Responses

机译：Dj-1 / park7是缺氧诱导的细胞反应的重要介质。

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In cancer, DJ-1/PARK7 acts as an oncogene that drives Akt-medi-ated cell survival. Although amplification of DJ-1 has been described in several types of tumors, the mechanistic basis of DJ-1's oncogenic effect remains incompletely understood. A tumor's ability to adapt to hypoxia is absolutely critical for its survival and progression, and this adaptation is largely mediated by the transcription factor HIF1. The stabilization of HIF1 subunits during hypoxia is at least partly dependent on the PI3K/Akt/mTOR pathway. We hypothesized that DJ-1, a positive regulator of Akt when over-expressed, might be involved in regulating HIF1 transcrip-tional activity under hypoxic conditions. Our results show that loss of DJ-1 in human cell lines and transformed mouse fibroblasts decreases the transcription of a variety of HIF1-responsive genes during hypoxia. Moreover, DJ-1 expression is critical for the Akt and mTOR activities that sustain HIF1 stability. Surprisingly, DJ-1 also regulates the activity of the metabolic sensor AMPK, especially during hypoxia. Finally, DJ-1 appears to protect cells against hypoxia-induced cell death and is required for their adaptation to severe hypoxic stress. Our work positions DJ-1 as an upstream activator of HIF1 function in cancer cells and establishes that DJ-1's oncogenic activity stems from its ability to increase a cell's resistance to hypoxic stress through DJ-1's regulatory effects on mTOR and AMPK. The discovery of these functions of DJ-1 strengthens the case for the development of therapeutics that target DJ-1 activity in cancer cells.
机译：在癌症中，DJ-1 / PARK7充当致癌基因，可驱动Akt介导的细胞存活。尽管已经在几种类型的肿瘤中描述了DJ-1的扩增，但对DJ-1致癌作用的机理基础尚不完全清楚。肿瘤适应缺氧的能力对其生存和进展至关重要，这种适应主要由转录因子HIF1介导。缺氧期间HIF1亚基的稳定至少部分取决于PI3K / Akt / mTOR途径。我们假设，DJ-1是Akt的正向调节因子，当其过表达时，可能参与了低氧条件下HIF1转录活性的调节。我们的结果表明，在缺氧条件下，人细胞系和转化的小鼠成纤维细胞中DJ-1的丢失会降低各种HIF1反应基因的转录。此外，DJ-1表达对于维持HIF1稳定性的Akt和mTOR活性至关重要。出人意料的是，DJ-1还调节代谢传感器AMPK的活性，尤其是在缺氧期间。最后，DJ-1似乎可以保护细胞免受低氧诱导的细胞死亡，并且是其适应严重缺氧应激所必需的。我们的工作将DJ-1定位为癌细胞中HIF1功能的上游激活剂，并确定DJ-1的致癌活性源于其通过提高DJ-1对mTOR和AMPK的调节作用来增强细胞对低氧应激的抵抗力的能力。 DJ-1的这些功能的发现加强了针对癌细胞中DJ-1活性的治疗药物开发的理由。

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