15-Deoxy-Δ12,14-prostaglandin J2: The endogenous electrophile that induces neuronal apoptosis
- Mitsuhiro Kondo*,†,
- Takahiro Shibata*,†,
- Takeshi Kumagai*,
- Toshihiko Osawa*,
- Noriyuki Shibata‡,
- Makio Kobayashi‡,
- Shoichi Sasaki§,
- Makoto Iwata§,
- Noriko Noguchi¶, and
- Koji Uchida*,‖
- *Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan; Departments of ‡Pathology and §Neurology, Tokyo Women's Medical University, Tokyo 162-8666, Japan; and ¶Genome Sciences, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan
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Communicated by E. R. Stadtman, National Institutes of Health, Bethesda, MD (received for review January 29, 2002)
Abstract
Prostaglandin D2 (PGD2), a major cyclooxygenase product in a variety of tissues and cells, readily undergoes dehydration to yield the bioactive cyclopentenone-type PGs of the J2-series, such as 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2). The observation that the level of 15d-PGJ2 increased in the tissue cells from patients with sporadic amyotrophic lateral sclerosis suggested that the formation of 15d-PGJ2 may be closely associated with neuronal cell death during chronic inflammatory processes. In vitro experiments using SH-SY5Y human neuroblastoma cells revealed that 15d-PGJ2 induced apoptotic cell death. An oligonucleotide microarray analysis demonstrated that, in addition to the heat shock-responsive and redox-responsive genes, the p53-responsive genes, such as gadd45, cyclin G1, and cathepsin D, were significantly up-regulated in the cells treated with 15d-PGJ2. Indeed, the 15d-PGJ2 induced accumulation and phosphorylation of p53, which was accompanied by a preferential redistribution of the p53 protein in the nuclei of the cells and by a time-dependent increase in p53 DNA binding activity, suggesting that p53 accumulated in response to the treatment with 15d-PGJ2 was functional. The 15d-PGJ2-induced accumulation of p53 resulted in the activation of a death-inducing caspase cascade mediated by Fas and the Fas ligand.
Footnotes
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↵ † M.K. and T.S. contributed equally to this work.
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↵ ‖ To whom reprint requests should be addressed. E-mail: uchidak{at}agr.nagoya-u.ac.jp.
- Abbreviations:
- PGs,
- prostaglandins;
- 15d-PGJ2,
- 15-deoxy-Δ12,14-PGJ2;
- MTT,
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide;
- ALS,
- amyotrophic lateral sclerosis;
- FasL,
- Fas ligand;
- COX-2,
- cyclooxygenase-2;
- z-VAD-fmk,
- benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone;
- Ac-IETD-CHO,
- acetyl-Ile-Glu-Thr-Asp-CHO;
- PI,
- propidium iodide;
- RT,
- reverse transcription
- Copyright © 2002, The National Academy of Sciences
