Acetylation of the pro-apoptotic factor, p53 in the hippocampus following cerebral ischemia and modulation by estrogen

Limor Raz, Quanguang Zhang, Dong Han, Yan Dong, Liesl de Sevilla, Darrell W Brann

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background: Recent studies demonstrate that acetylation of the transcription factor, p53 on lysine 373 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, 17β-estradiol (17β-E 2), and thus, this study examined these issues. Methodology/Principal Findings: The study revealed that Acetyl p53-Lysine 373 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 17β-E 2. 17β-E 2 also enhanced interaction of p53 with the ubiquitin ligase, Mdm2, increased ubiquitination of p53, and induced its down-regulation, as well as attenuated elevation of the p53 transcriptional target, Puma. We also observed enhanced acetylation of p53 at a different lysine (Lys 382) at 3 h after reperfusion, and 17β-E 2 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 17β-E 2 to attenuate p53 acetylation was lost, and intriguingly, Acetyl p53-Lysine 373 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, 17β-E 2, markedly attenuates the ischemia-induced p53 acetylation. Furthermore, following LTED, the suppressive effect of 17β-E 2 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.

Original languageEnglish (US)
Article numbere27039
JournalPloS one
Volume6
Issue number10
DOIs
StatePublished - Nov 2 2011

Fingerprint

Acetylation
acetylation
hippocampus
ischemia
Brain Ischemia
estrogens
Hippocampus
Estrogens
Modulation
Lysine
lysine
Puma
Hippocampal CA1 Region
Reperfusion
Animals
acetyltransferases
NADPH Oxidase
Ubiquitination
Neuroprotective Agents
Ligases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Acetylation of the pro-apoptotic factor, p53 in the hippocampus following cerebral ischemia and modulation by estrogen. / Raz, Limor; Zhang, Quanguang; Han, Dong; Dong, Yan; de Sevilla, Liesl; Brann, Darrell W.

In: PloS one, Vol. 6, No. 10, e27039, 02.11.2011.

Research output: Contribution to journalArticle

@article{12291214ffa5467b9447c54a5ef23499,
title = "Acetylation of the pro-apoptotic factor, p53 in the hippocampus following cerebral ischemia and modulation by estrogen",
abstract = "Background: Recent studies demonstrate that acetylation of the transcription factor, p53 on lysine 373 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, 17β-estradiol (17β-E 2), and thus, this study examined these issues. Methodology/Principal Findings: The study revealed that Acetyl p53-Lysine 373 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 17β-E 2. 17β-E 2 also enhanced interaction of p53 with the ubiquitin ligase, Mdm2, increased ubiquitination of p53, and induced its down-regulation, as well as attenuated elevation of the p53 transcriptional target, Puma. We also observed enhanced acetylation of p53 at a different lysine (Lys 382) at 3 h after reperfusion, and 17β-E 2 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 17β-E 2 to attenuate p53 acetylation was lost, and intriguingly, Acetyl p53-Lysine 373 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, 17β-E 2, markedly attenuates the ischemia-induced p53 acetylation. Furthermore, following LTED, the suppressive effect of 17β-E 2 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.",
author = "Limor Raz and Quanguang Zhang and Dong Han and Yan Dong and {de Sevilla}, Liesl and Brann, {Darrell W}",
year = "2011",
month = "11",
day = "2",
doi = "10.1371/journal.pone.0027039",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Acetylation of the pro-apoptotic factor, p53 in the hippocampus following cerebral ischemia and modulation by estrogen

AU - Raz, Limor

AU - Zhang, Quanguang

AU - Han, Dong

AU - Dong, Yan

AU - de Sevilla, Liesl

AU - Brann, Darrell W

PY - 2011/11/2

Y1 - 2011/11/2

N2 - Background: Recent studies demonstrate that acetylation of the transcription factor, p53 on lysine 373 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, 17β-estradiol (17β-E 2), and thus, this study examined these issues. Methodology/Principal Findings: The study revealed that Acetyl p53-Lysine 373 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 17β-E 2. 17β-E 2 also enhanced interaction of p53 with the ubiquitin ligase, Mdm2, increased ubiquitination of p53, and induced its down-regulation, as well as attenuated elevation of the p53 transcriptional target, Puma. We also observed enhanced acetylation of p53 at a different lysine (Lys 382) at 3 h after reperfusion, and 17β-E 2 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 17β-E 2 to attenuate p53 acetylation was lost, and intriguingly, Acetyl p53-Lysine 373 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, 17β-E 2, markedly attenuates the ischemia-induced p53 acetylation. Furthermore, following LTED, the suppressive effect of 17β-E 2 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.

AB - Background: Recent studies demonstrate that acetylation of the transcription factor, p53 on lysine 373 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, 17β-estradiol (17β-E 2), and thus, this study examined these issues. Methodology/Principal Findings: The study revealed that Acetyl p53-Lysine 373 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 17β-E 2. 17β-E 2 also enhanced interaction of p53 with the ubiquitin ligase, Mdm2, increased ubiquitination of p53, and induced its down-regulation, as well as attenuated elevation of the p53 transcriptional target, Puma. We also observed enhanced acetylation of p53 at a different lysine (Lys 382) at 3 h after reperfusion, and 17β-E 2 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 17β-E 2 to attenuate p53 acetylation was lost, and intriguingly, Acetyl p53-Lysine 373 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, 17β-E 2, markedly attenuates the ischemia-induced p53 acetylation. Furthermore, following LTED, the suppressive effect of 17β-E 2 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.

UR - http://www.scopus.com/inward/record.url?scp=80055034825&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80055034825&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0027039

DO - 10.1371/journal.pone.0027039

M3 - Article

C2 - 22046440

AN - SCOPUS:80055034825

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e27039

ER -