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Consequences of DJ-1 upregulation following p53 loss and cell transformation

Oncogene volume 31, pages 664–670 (2012)Cite this article

Abstract

p53 is a tumor suppressor that responds to various stress signals by initiating cell-cycle arrest, senescence and apoptosis. Mutations of the p53 gene are found in over 50% of human tumors, highlighting the importance of p53 in tumor suppression. Numerous studies have reported on the interactions between p53, IGF-1–AKT and mTOR pathways as potentially explaining some of the tumor suppressive activities of p53. To further understand the basis of these interactions, we analyzed the involvement of DJ-1, an oncogene known to drive AKT-mediated cell survival, in the p53–AKT axis. In this study, we show that DJ-1 and p53 are tightly ‘linked’: p53 prevents the accumulation of DJ-1 protein, whereas loss of p53 leads to stabilization and enhancement of DJ-1 expression. Interestingly, this increase in DJ-1 level is only observed when p53 loss is accompanied by transformation of cells. Moreover, DJ-1 seems to be required for the enhanced activation of AKT observed in p53-deficient cells. Such observation confers a new property to DJ-1 associated to transforming-process to its oncogenic ability to drive AKT activation. We also show that DJ-1 is necessary for p53 activation following oxidative stress, suggesting the existence of a finely regulated loop between these two proteins in transformed cells. Finally, we demonstrate that in the absence of p53, DJ-1 is stabilized by ROS accumulation, and surprisingly seems to be required for this high intracellular ROS production. These data offer new insights into the regulation of DJ-1 and suggest that DJ-1 is a target of p53. Importantly, our study highlights that during transformation, DJ-1 is having a key role in the p53-regulated AKT pathway and p53-driven oxidative-stress response.

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Acknowledgements

We thank P Spoto and K Sari for technical assistance. S Vasseur, R Tomasini, and J Tardivel-Lacombe were supported by Institute National de la Santé et de la Recherche Médicale France. F Guillaumond was supported by the ‘Fondation Santé, Sport et développement durable’. S Vasseur and S Afzal were supported by the Canadian Institute of Health Research. This work was also supported by grants from the ‘Ligue Contre le Cancer’, France and the ‘Institut National du Cancer (INCa)’, France.

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  1. Institut National de la Santé et de la Recherche Médicale Unité, Marseille, 624, France

    S Vasseur, R Tomasini, F Guillaumond, J Tardivel-Lacombe & J L Iovanna

  2. Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

    S Vasseur, S Afzal & T W Mak

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  1. S Vasseur
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  2. S Afzal
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Correspondence to T W Mak or J L Iovanna.

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Vasseur, S., Afzal, S., Tomasini, R. et al. Consequences of DJ-1 upregulation following p53 loss and cell transformation. Oncogene 31, 664–670 (2012). https://doi.org/10.1038/onc.2011.268

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