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Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease

Nature Cell Biology volume 11, pages 1370–1375 (2009)Cite this article

Abstract

Mutations of the ubiquitin ligase parkin account for most autosomal recessive forms of juvenile Parkinson's disease (AR-JP). Several studies have suggested that parkin possesses DNA-binding and transcriptional activity. We report here that parkin is a p53 transcriptional repressor. First, parkin prevented 6-hydroxydopamine-induced caspase-3 activation in a p53-dependent manner. Concomitantly, parkin reduced p53 expression and activity, an effect abrogated by familial parkin mutations known to either abolish or preserve its ligase activity. ChIP experiments indicate that overexpressed and endogenous parkin interact physically with the p53 promoter and that pathogenic mutations abolish DNA binding to and promoter transactivation of p53. Parkin lowered p53 mRNA levels and repressed p53 promoter transactivation through its Ring1 domain. Conversely, parkin depletion enhanced p53 expression and mRNA levels in fibroblasts and mouse brains, and increased cellular p53 activity and promoter transactivation in cells. Finally, familial parkin missense and deletion mutations enhanced p53 expression in human brains affected by AR-JP. This study reveals a ubiquitin ligase-independent function of parkin in the control of transcription and a functional link between parkin and p53 that is altered by AR-JP mutations.

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Figure 1: Protective effect of parkin is associated with modulation of p53 in TSM1 neuronal cell line.
Figure 2: p53 pathway is upregulated in parkin-deficient fibroblasts and mouse brains.
Figure 3: Mutations associated with familial Parkinson's disease abolish the ability of parkin to control p53 and do not rescue parkin function in parkin-deficient fibroblasts.
Figure 4: Deletion analysis of p53 promoter transactivation by parkin and physical interaction between parkin and p53 promoter.
Figure 5: Mapping of the parkin domain involved p53 transcription repression.

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Acknowledgements

We would like to thank Amanda Patel for helpful discussion concerning gel shift analyses. We wish to thank M. Oren, B. Vogelstein and T. Dawson for providing us with the p53 promoter, PG13 and parkin-deleted constructs. M. Roussel and T. Dawson are thanked for providing the p19Arf–1−/− and p19Arf–1−/−p53−/− and parkin knockout cells, and parkin-deletion constructs, respectively. We thank J. C. Bourdon for providing polyclonal p53-directed antibodies. We wish to thank F. Brau for help in confocal analysis and F. Aguila for artwork. This work was supported by the Fondation pour la Recherche Médicale.

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Authors and Affiliations

  1. Institut de Pharmacologie Moléculaire et Cellulaire and Institut de NeuroMédecine Moléculaire, UMR6097 CNRS/UNSA, Équipe labellisée Fondation pour la Recherche Médicale, 660 Route des Lucioles, Valbonne, 06560, France

    Cristine Alves da Costa, Claire Sunyach, Emilie Giaime & Frédéric Checler

  2. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, 21287, MD, USA

    Andrew West

  3. INSERM U679, Hôpital de la Pitié-Salpêtrière, 47 boulevard de l'Hôpital, Paris, 75013, France

    Olga Corti & Alexis Brice

  4. Center for Environmental & Genetic Medicine, Institute of Biosciences & Technology, Houston, USA

    Stephen Safe

  5. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Patrick M. Abou-Sleiman & Nicholas W. Wood

  6. Brain Research Institute, University of Niigata, 1-757 Asahimachi, Niigata, 951-8585, Japan

    Hitoshi Takahashi

  7. Center of Neurological Diseases, Harvard Medical School, Boston, Massachusetts, USA

    Mathew S. Goldberg & Jie Shen

Authors
  1. Cristine Alves da Costa
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  2. Claire Sunyach
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Contributions

S.C. and E.G. performed a subset of experiments and contributed equally to the work; A.W. performed lentiviral experiments; O.C. and A.B. provided parkin cDNA; N.W.W. and P.M.A.S. provided 'English' human brain samples; H.T. provided 'Japanese' human brain samples; M.S.G. and J.S. provided parkin-null fibroblasts and brains; S.S. provided p53 promoter constructs; C.A.C. and F.C. are co-senior contributors; C.A.C. designed the study, performed most of the experiments, discussed data and wrote the manuscript; F.C. discussed data and contributed to the writing of the manuscript.

Corresponding authors

Correspondence to Cristine Alves da Costa or Frédéric Checler.

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da Costa, C., Sunyach, C., Giaime, E. et al. Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. Nat Cell Biol 11, 1370–1375 (2009). https://doi.org/10.1038/ncb1981

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