15-Deoxy-Delta(12,14)-prostaglandin J(2): the endogenous electrophile that induces neuronal apoptosis.
Prostaglandin D(2) (PGD(2)), a major cyclooxygenase product in a variety of tissues and cells, readily undergoes dehydration to yield the bioactive cyclopentenone-type PGs of the J(2)-series, such as 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). The observation that the level of 15d-PGJ(2) increased in the tissue cells from patients with sporadic amyotrophic lateral sclerosis suggested that the formation of 15d-PGJ(2) may be closely associated with neuronal cell death during chronic inflammatory processes. In vitro experiments using SH-SY5Y human neuroblastoma cells revealed that 15d-PGJ(2) 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-PGJ(2). Indeed, the 15d-PGJ(2) 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-PGJ(2) was functional. The 15d-PGJ(2)-induced accumulation of p53 resulted in the activation of a death-inducing caspase cascade mediated by Fas and the Fas ligand.
Kondo
Mitsuhiro
M
Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
Shibata
Takahiro
T
Kumagai
Takeshi
T
Osawa
Toshihiko
T
Shibata
Noriyuki
N
Kobayashi
Makio
M
Sasaki
Shoichi
S
Iwata
Makoto
M
Noguchi
Noriko
N
Uchida
Koji
K
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D007155:Immunologic Factors; D016159:Tumor Suppressor Protein p53; D015230:Prostaglandin D2