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Glioma tumor grade correlates with parkin depletion in mutant p53-linked tumors and results from loss of function of p53 transcriptional activity

Oncogene volume 33, pages 1764–1775 (2014)Cite this article

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Abstract

Gliomas represent the most frequent form of primary brain tumors in adults, the prognosis of which remains extremely poor. Inactivating mutations on the tumor suppressor TP53 were proposed as a key etiological trigger of glioma development. p53 has been recently identified as a transcriptional target of parkin. Interestingly, somatic mutations on parkin have also been linked to glioma genesis. We examined the possibility that a disruption of a functional interaction between p53 and parkin could contribute to glioma development in samples devoid of somatic parkin mutations or genetic allele deletion. We show here that parkin levels inversely correlate to brain tumor grade and p53 levels in oligodendrogliomas, mixed gliomas and glioblastomas. We demonstrate that p53 levels negatively and positively correlate to bax and Bcl2 respectively, underlying a loss of p53 transcriptional activity in all types of glial tumors. Using various cell models lacking p53 or harboring either transcriptionally inactive or dominant negative p53, as well as in p53 knockout mice brain, we establish that p53 controls parkin promoter transactivation, mRNA and protein levels. Furthermore, we document an increase of parkin expression in mice brain after p53-bearing viral infection. Finally, both cancer-related p53 inactivating mutations and deletion of a consensus p53 binding sequence located on parkin promoter abolish p53-mediated control of parkin transcription, demonstrating that p53 regulates parkin transcription via its DNA binding properties. In conclusion, our work delineates a functional interplay between mutated p53 and parkin in glioma genesis that is disrupted by cancer-linked pathogenic mutations. It also allows envisioning parkin as a novel biomarker of glioma biopsies enabling to follow the progression of this type of cancers.

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Acknowledgements

Drs Roussel, Bourdon and Serrano are thanked for providing us with p53 knockout cells, MCF-7 cells and mice brains. Drs West and Oren are acknowledged for providing us with parkin-luciferase and PG13 constructs. JV was supported by AMPA (Association Monégasque Pour la recherche sur la Maladie d’Alzheimer) and ARC («Association pour la recherche contre le cancer»). This work was supported by the ‘Fondation pour la Recherche Médicale’ and by the ‘Conseil Général des Alpes Maritimes’. This work has been developed and supported through the LABEX (excellence laboratory, program investment for the future) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer’s disease). Cristine Alves da Costa is recipient of a Hospital Contract for Translational Research (CHRT) between INSERM and the Hospices Civils de Lyon.

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Authors and Affiliations

  1. Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled ‘Fondation pour la Recherche Médicale’ and ‘Laboratory of Excellence (LABEX) Distalz’, Valbonne, France

    J Viotti, E Duplan, C Caillava, J Condat, T Goiran, C Giordano, F Checler & C Alves da Costa

  2. AP-HP, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre & Marie Curie Paris VI, Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, UMRS 975, Paris, France

    Y Marie, A Idbaih & J-Y Delattre

  3. Centre de référence des maladies rares «syndromes neurologiques paranéoplasiques», hospices civils de Lyon, hôpital neurologique, Lyon, France

    J Honnorat

  4. Inserm U1028/CNRS UMR 5292, centre de recherche en neuroscience de Lyon, Lyon, France

    J Honnorat

  5. Université de Lyon, Université Claude-Bernard Lyon-1, Lyon, France

    J Honnorat

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  1. J Viotti
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Correspondence to F Checler or C Alves da Costa.

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Viotti, J., Duplan, E., Caillava, C. et al. Glioma tumor grade correlates with parkin depletion in mutant p53-linked tumors and results from loss of function of p53 transcriptional activity. Oncogene 33, 1764–1775 (2014). https://doi.org/10.1038/onc.2013.124

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