title: The caspase 6 derived N-terminal fragment of DJ-1 promotes apoptosis via increased ROS production.
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.
authors.affiliation: INSERM U1065, Team 2: Morts Cellulaires, Differentiation et Cancer, Nice, France.
authors.forename: G
authors.initials: G
authors.lastname: Robert
authors.forename: A
authors.initials: A
authors.lastname: Puissant
authors.forename: M
authors.initials: M
authors.lastname: Dufies
authors.forename: S
authors.initials: S
authors.lastname: Marchetti
authors.forename: A
authors.initials: A
authors.lastname: Jacquel
authors.forename: T
authors.initials: T
authors.lastname: Cluzeau
authors.forename: P
authors.initials: P
authors.lastname: Colosetti
authors.forename: N
authors.initials: N
authors.lastname: Belhacene
authors.forename: P
authors.initials: P
authors.lastname: Kahle
authors.forename: C A
authors.initials: CA
authors.lastname: Da Costa
authors.forename: F
authors.initials: F
authors.lastname: Luciano
authors.forename: F
authors.initials: F
authors.lastname: Checler
authors.forename: P
authors.initials: P
authors.lastname: Auberger
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053178:Caspase 6 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D000071617:Protein Deglycase DJ-1; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D053178:Caspase 6; D019311:Staurosporine; D015655:1-Methyl-4-phenylpyridinium