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

Publication ,  Journal Article
da Costa, CA; Sunyach, C; Giaime, E; West, A; Corti, O; Brice, A; Safe, S; Abou-Sleiman, PM; Wood, NW; Takahashi, H; Goldberg, MS; Shen, J; Checler, F
Published in: Nat Cell Biol
November 2009

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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Published In

Nat Cell Biol

DOI

EISSN

1476-4679

Publication Date

November 2009

Volume

11

Issue

11

Start / End Page

1370 / 1375

Location

England

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Transcription, Genetic
  • Promoter Regions, Genetic
  • Parkinson Disease
  • Mutation
  • Humans
  • Genes, p53
  • Genes, Recessive
  • Developmental Biology
  • Adolescent
 

Citation

APA
Chicago
ICMJE
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da Costa, C. A., Sunyach, C., Giaime, E., West, A., Corti, O., Brice, A., … Checler, F. (2009). Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. Nat Cell Biol, 11(11), 1370–1375. https://doi.org/10.1038/ncb1981
Costa, Cristine Alves da, Claire Sunyach, Emilie Giaime, Andrew West, Olga Corti, Alexis Brice, Stephen Safe, et al. “Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease.Nat Cell Biol 11, no. 11 (November 2009): 1370–75. https://doi.org/10.1038/ncb1981.
da Costa CA, Sunyach C, Giaime E, West A, Corti O, Brice A, et al. Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. Nat Cell Biol. 2009 Nov;11(11):1370–5.
da Costa, Cristine Alves, et al. “Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease.Nat Cell Biol, vol. 11, no. 11, Nov. 2009, pp. 1370–75. Pubmed, doi:10.1038/ncb1981.
da Costa CA, Sunyach C, Giaime E, West A, Corti O, Brice A, Safe S, Abou-Sleiman PM, Wood NW, Takahashi H, Goldberg MS, Shen J, Checler F. Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. Nat Cell Biol. 2009 Nov;11(11):1370–1375.

Published In

Nat Cell Biol

DOI

EISSN

1476-4679

Publication Date

November 2009

Volume

11

Issue

11

Start / End Page

1370 / 1375

Location

England

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • Transcription, Genetic
  • Promoter Regions, Genetic
  • Parkinson Disease
  • Mutation
  • Humans
  • Genes, p53
  • Genes, Recessive
  • Developmental Biology
  • Adolescent