Prostate apoptosis response-4 mediates trophic factor withdrawal-induced apoptosis of hippocampal neurons: actions prior to mitochondrial dysfunction and caspase activation.
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.
Chan
S L
SL
Sanders-Brown Research Center on Aging and Department of Physiology, University of Kentucky, Lexington 40536-0230, USA.
Tammariello
S P
SP
Estus
S
S
Mattson
M P
MP
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016375:Antisense Elements (Genetics); D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007425:Intracellular Membranes / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020112:Rhodamine 123; D012235:Rhodamines; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D016375:Antisense Elements (Genetics); D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D002843:Chromatin; D005609:Free Radicals; D006133:Growth Substances; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012235:Rhodamines; D017392:Thiobarbituric Acid Reactive Substances; C101296:prostate apoptosis response-4 protein; C058319:dihydrorhodamine 123; D014810:Vitamin E; D020112:Rhodamine 123; D014527:Uric Acid; D004958:Estradiol; D020169:Caspases