ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1
Autor: | Emilie Giaime, Cristine Alves da Costa, Hiroyoshi Ariga, Julien Viotti, Ling Qi, Jean Sevalle, Frédéric Checler, Alexis Brice, Eric Duplan, Olga Corti |
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Jazyk: | angličtina |
Rok vydání: | 2013 |
Předmět: |
X-Box Binding Protein 1
Transcription Genetic Ubiquitin-Protein Ligases Protein Deglycase DJ-1 Regulatory Factor X Transcription Factors Biology Parkin law.invention Mice Transcription (biology) law In vivo Cell Line Tumor Animals Humans Oncogene Proteins Messenger RNA Endoplasmic reticulum Binding protein Intracellular Signaling Peptides and Proteins Parkinson Disease Cell Biology Peroxiredoxins Endoplasmic Reticulum Stress Molecular biology Mice Mutant Strains nervous system diseases DNA-Binding Proteins HEK293 Cells Gene Expression Regulation Unfolded protein response Suppressor Tumor Suppressor Protein p53 Research Article Signal Transduction Transcription Factors |
Popis: | Parkin and DJ-1 are two multi-functional proteins linked to autosomal recessive early-onset Parkinson's disease (PD) that have been shown to functionally interact by as-yet-unknown mechanisms. We have delineated the mechanisms by which parkin controls DJ-1. Parkin modulates DJ-1 transcription and protein levels via a signaling cascade involving p53 and the endoplasmic reticulum (ER)-stress-induced active X-box-binding protein-1S (XBP-1S). Parkin triggers the transcriptional repression of p53 while p53 downregulates DJ-1 protein and mRNA expressions. We show that parkin-mediated control of DJ-1 is fully p53-dependent. Furthermore, we establish that p53 lowers the protein and mRNA levels of XBP-1S. Accordingly, we show that parkin ultimately upregulates XBP-1 levels. Subsequently, XBP-1S physically interacts with the DJ-1 promoter, thereby enhancing its promoter trans-activation, mRNA levels and protein expression. This data was corroborated by the examination of DJ-1 in both parkin- and p53-null mice brains. This transcriptional cascade is abolished by pathogenic parkin mutations and is independent of its ubiquitin-ligase activity. Our data establish a parkin-dependent ER-stress-associated modulation of DJ-1 and identifies p53 and XBP-1 as two major actors acting downstream of parkin in this signaling cascade in cells and in vivo. This work provides a mechanistic explanation for the increase in the unfolded protein response observed in PD pathology, i.e. that it is due to a defect in parkin-associated control of DJ-1. |
Databáze: | OpenAIRE |
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