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- Title
The caspase 6 derived N-terminal fragment of DJ-1 promotes apoptosis via increased ROS production.
- Authors
Robert, G; Puissant, A; Dufies, M; Marchetti, S; Jacquel, A; Cluzeau, T; Colosetti, P; Belhacene, N; Kahle, P; Da Costa, C A; Luciano, F; Checler, F; Auberger, P
- Abstract
In pathological conditions, the amount of DJ-1 determines whether a cell can survive or engage a cell death program. This is exemplified in epithelial cancers, in which DJ-1 expression is increased, while autosomal recessive early onset Parkinson's disease mutations of DJ-1 generally lead to decreased stability and expression of the protein. We have shown previously that DJ-1 is cleaved by caspase-6 during induction of apoptosis. We demonstrate here that the N-terminal cleaved fragment of DJ-1 (DJ-1 Nt) is specifically expressed in the nucleus and promotes apoptosis in SH-SY5Y neuroblastoma cell lines. In addition, overexpression of DJ-1 Nt in different cell lines leads to a loss of clonogenic potential and sensitizes to staurosporin and 1-methyl-4-phenylpyridinium (MPP+)-mediated caspase activation and apoptosis. Importantly, inhibition of endogenous DJ-1 expression with sh-RNA or DJ-1 deficiency mimics the effect of DJ-1 Nt on cell growth and apoptosis. Moreover, overexpression of DJ-1 Nt increases reactive oxygen species (ROS) production, and sensitizes to MPP+-mediated apoptosis and DJ-1 oxidation. Finally, specific exclusion of DJ-1 Nt from the nucleus abrogates its pro-apoptotic effect. Taken together, our findings identify an original pathway by which generation of a nuclear fragment of DJ-1 through caspase 6-mediated cleavage induces ROS-dependent amplification of apoptosis.
- Subjects
CARCINOMA; PARKINSON'S disease; REACTIVE oxygen species; APOPTOSIS; NEUROBLASTOMA; CELL lines; STAUROSPORINE
- Publication
Cell Death & Differentiation, 2012, Vol 19, Issue 11, p1769
- ISSN
1350-9047
- Publication type
Article
- DOI
10.1038/cdd.2012.55