Abstract
Prostate apoptosis response-4 (Par-4) is the product of a gene up-regulated in prostate cancer cells undergoing apoptosis. We now report that Par-4 mRNA and protein levels rapidly and progressively increase 4-24 h following trophic factor withdrawal (TFW) in cultured embryonic rat hippocampal neurons. The increased Par-4 levels follow an increase of reactive oxygen species, and precede mitochondrial membrane depolarization, caspase activation, and nuclear chromatin condensation/fragmentation. Pretreatment of cultures with 17beta-estradiol, vitamin E, and uric acid largely prevented Par-4 induction and cell death following TFW, demonstrating necessary roles for oxidative stress and membrane lipid peroxidation in TFW-induced neuronal apoptosis. Par-4 antisense oligonucleotide treatment blocked Par-4 protein increases and attenuated mitochondrial dysfunction, caspase activation, and cell death following TFW. Collectively, our data identify Par-4 as an early and pivotal player in neuronal apoptosis resulting from TFW and suggest that estrogen and antioxidants may prevent apoptosis, in part, by suppressing Par-4 production.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antioxidants / pharmacology
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Antisense Elements (Genetics)
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Caspases / metabolism*
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Chromatin / metabolism
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Estradiol / pharmacology
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Free Radicals / metabolism
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Gene Expression / drug effects
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Growth Substances / pharmacology
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Hippocampus / cytology
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Intracellular Membranes / physiology
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Intracellular Signaling Peptides and Proteins*
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Membrane Potentials / physiology
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Mitochondria / metabolism*
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Neurons / cytology*
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Neurons / enzymology
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Nuclear Proteins / metabolism
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Oxidative Stress / physiology
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RNA, Messenger / metabolism
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Rats
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Rhodamine 123
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Rhodamines
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Thiobarbituric Acid Reactive Substances / metabolism
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Uric Acid / pharmacology
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Vitamin E / pharmacology
Substances
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Antioxidants
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Antisense Elements (Genetics)
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Apoptosis Regulatory Proteins
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Carrier Proteins
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Chromatin
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Free Radicals
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Growth Substances
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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RNA, Messenger
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Rhodamines
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Thiobarbituric Acid Reactive Substances
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prostate apoptosis response-4 protein
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dihydrorhodamine 123
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Vitamin E
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Rhodamine 123
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Uric Acid
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Estradiol
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Caspases