Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease.
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.
da Costa
Cristine Alves
CA
Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097 CNRS/UNSA, Equipe labellisée Fondation pour la Recherche Médicale, 660 Route des Lucioles, 06560, Valbonne, France. acosta@ipmc.cnrs.fr
Sunyach
Claire
C
Giaime
Emilie
E
West
Andrew
A
Corti
Olga
O
Brice
Alexis
A
Safe
Stephen
S
Abou-Sleiman
Patrick M
PM
Wood
Nicholas W
NW
Takahashi
Hitoshi
H
Goldberg
Mathew S
MS
Shen
Jie
J
Checler
Frédéric
F
D000293:Adolescent; D005808:Genes, Recessive; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein