Acetylation of the Pro-Apoptotic Factor, p53 in the Hippocampus following Cerebral Ischemia and Modulation by Estrogen

Hdl Handle:
http://hdl.handle.net/10675.2/763
Title:
Acetylation of the Pro-Apoptotic Factor, p53 in the Hippocampus following Cerebral Ischemia and Modulation by Estrogen
Authors:
Raz, Limor; Zhang, Quan-Guang; Han, Dong; Dong, Yan; De Sevilla, Liesl; Brann, Darrell W ( 0000-0002-4480-8859 )
Abstract:
Background: Recent studies demonstrate that acetylation of the transcription factor, p53 on lysine373 leads to its enhanced stabilization/activity and increased susceptibility of cells to stress. However, it is not known whether acetylation of p53 is altered in the hippocampus following global cerebral ischemia (GCI) or is regulated by the hormone, 17b-estradiol (17b2E2), and thus, this study examined these issues.; Methodology/Principal Findings: The study revealed that Acetyl p53-Lysine373 levels were markedly increased in the hippocampal CA1 region after GCI at 3 h, 6 h and 24 h after reperfusion, an effect strongly attenuated by 17b2E2. 17b2E2 also enhanced interaction of p53 with the ubiquitin ligase, Mdm2, increased ubiquitination of p53, and induced its downregulation, as well as attenuated elevation of the p53 transcriptional target, Puma. We also observed enhanced acetylation of p53 at a different lysine (Lys382) at 3 h after reperfusion, and 17b2E2 also markedly attenuated this effect. Furthermore, administration of an inhibitor of CBP/p300 acetyltransferase, which acetylates p53, was strongly neuroprotective of the CA1 region following GCI. In long-term estrogen deprived (LTED) animals, the ability of 17b2E2 to attenuate p53 acetylation was lost, and intriguingly, Acetyl p53-Lysine373 levels were markedly elevated in sham (non-ischemic) LTED animals. Finally, intracerebroventricular injections of Gp91ds-Tat, a specific NADPH oxidase (NOX2) inhibitor, but not the scrambled tat peptide control (Sc-Tat), attenuated acetylation of p53 and reduced levels of Puma following GCI.; Conclusions/Significance: The studies demonstrate that p53 undergoes enhanced acetylation in the hippocampal CA1 region following global cerebral ischemia, and that the neuroprotective agent, 17b2E2, markedly attenuates the ischemiainduced p53 acetylation. Furthermore, following LTED, the suppressive effect of 17b2E2 on p53 acetylation is lost, and p53 acetylation increases in the hippocampus, which may explain previous reports of increased sensitivity of the hippocampus to ischemic stress following LTED.
Citation:
PLoS One. 2011 Oct 26; 6(10):e27039
Issue Date:
26-Oct-2011
URI:
http://hdl.handle.net/10675.2/763
DOI:
10.1371/journal.pone.0027039
PubMed ID:
22046440
PubMed Central ID:
PMC3202599
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Institute of Molecular Medicine and Genetics: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorRaz, Limoren_US
dc.contributor.authorZhang, Quan-Guangen_US
dc.contributor.authorHan, Dongen_US
dc.contributor.authorDong, Yanen_US
dc.contributor.authorDe Sevilla, Lieslen_US
dc.contributor.authorBrann, Darrell Wen_US
dc.date.accessioned2012-10-26T20:30:40Z-
dc.date.available2012-10-26T20:30:40Z-
dc.date.issued2011-10-26en_US
dc.identifier.citationPLoS One. 2011 Oct 26; 6(10):e27039en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22046440en_US
dc.identifier.doi10.1371/journal.pone.0027039en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/763-
dc.description.abstractBackground: Recent studies demonstrate that acetylation of the transcription factor, p53 on lysine373 leads to its enhanced stabilization/activity and increased susceptibility of cells to stress. However, it is not known whether acetylation of p53 is altered in the hippocampus following global cerebral ischemia (GCI) or is regulated by the hormone, 17b-estradiol (17b2E2), and thus, this study examined these issues.en_US
dc.description.abstractMethodology/Principal Findings: The study revealed that Acetyl p53-Lysine373 levels were markedly increased in the hippocampal CA1 region after GCI at 3 h, 6 h and 24 h after reperfusion, an effect strongly attenuated by 17b2E2. 17b2E2 also enhanced interaction of p53 with the ubiquitin ligase, Mdm2, increased ubiquitination of p53, and induced its downregulation, as well as attenuated elevation of the p53 transcriptional target, Puma. We also observed enhanced acetylation of p53 at a different lysine (Lys382) at 3 h after reperfusion, and 17b2E2 also markedly attenuated this effect. Furthermore, administration of an inhibitor of CBP/p300 acetyltransferase, which acetylates p53, was strongly neuroprotective of the CA1 region following GCI. In long-term estrogen deprived (LTED) animals, the ability of 17b2E2 to attenuate p53 acetylation was lost, and intriguingly, Acetyl p53-Lysine373 levels were markedly elevated in sham (non-ischemic) LTED animals. Finally, intracerebroventricular injections of Gp91ds-Tat, a specific NADPH oxidase (NOX2) inhibitor, but not the scrambled tat peptide control (Sc-Tat), attenuated acetylation of p53 and reduced levels of Puma following GCI.en_US
dc.description.abstractConclusions/Significance: The studies demonstrate that p53 undergoes enhanced acetylation in the hippocampal CA1 region following global cerebral ischemia, and that the neuroprotective agent, 17b2E2, markedly attenuates the ischemiainduced p53 acetylation. Furthermore, following LTED, the suppressive effect of 17b2E2 on p53 acetylation is lost, and p53 acetylation increases in the hippocampus, which may explain previous reports of increased sensitivity of the hippocampus to ischemic stress following LTED.en_US
dc.rightsRaz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectAnatomy and Physiologyen_US
dc.subjectEndocrine Systemen_US
dc.subjectEndocrine Physiologyen_US
dc.subjectEndocrine Cellsen_US
dc.subjectHormonesen_US
dc.subjectNeuroendocrinologyen_US
dc.subjectNeuroscienceen_US
dc.subjectMolecular Neuroscienceen_US
dc.subjectSignaling Pathwaysen_US
dc.titleAcetylation of the Pro-Apoptotic Factor, p53 in the Hippocampus following Cerebral Ischemia and Modulation by Estrogenen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3202599en_US
dc.contributor.corporatenameInstitute of Molecular Medicine and Genetics-

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