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DJ-1/PARK7 Is an Important Mediator of Hypoxia-Induced Cellular Responses
Sophie Vasseur, Samia Afzal, Joël Tardivel-Lacombe, David S. Park, Juan Lucio Iovanna and Tak Wah Mak
Proceedings of the National Academy of Sciences of the United States of America
Vol. 106, No. 4 (Jan. 27, 2009), pp. 1111-1116
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/40254691
Page Count: 6
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In cancer, DJ-1/PARK7 acts as an oncogene that drives Akt-mediated 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 transcriptional 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.
Proceedings of the National Academy of Sciences of the United States of America © 2009 National Academy of Sciences