17β-Estradiol Attenuates Proapoptotic p53/PUMA Signaling Pathway in Hippocampus CA1 following Global Ischemia
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1
Van der Veer Institute for Parkinson's and Brain Research, Institute of Molecular Medicine and Genetics, Developmental Neurobiology Program, Department of Neurology, United States
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2
Emory University, Biology Dep, United States
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3
St. Michaelâs College, Biology Dep, United States
17ß-Estradiol (E2) has been implicated to be neuroprotective against a variety of neurodegenerative diseases, including stroke. The current study examined whether E2 neuroprotection following global cerebral ischemia may involve an epigenetic mechanism to modulate acetylation/methylation (and thus activation) of the proapoptotic protein p53, and whether this could alter expression of the p53 downstream target, PUMA, a BH3 proapoptotic protein. Our results revealed that simultaneous epigenetic modifications of p53, including Lys acetylation (K373/K382) and Lys methylation (K372), are markedly increased in hippocampal CA1 neurons in placebo-treated animals 24h after reperfusion, as compared to sham controls. Intriguingly, E2 strongly attenuated the increase of both p53 post-translational modifications in CA1 neurons 24h after reperfusion, without affecting total p53 protein levels. The E2-induced attenuation of p53 acetylation/methylation suggests that p53 transcriptional activation may be diminished by E2 treatment. In support of this suggestion, Western blot and immunohistochemical studies revealed that protein expression of the p53 target gene, PUMA, was significantly enhanced in placebo-treated animals at 24h after reperfusion (as compared to sham controls), and that E2 strongly attenuated PUMA upregulation. As a whole, our studies suggest a novel epigenetic regulatory effect of E2 in stroke to modulate p53 activation and attenuate expression of the downstream proapoptotic target gene, PUMA, thereby providing an antiapoptotic mechanism for E2 neuroprotection. NINDS Grant # NS050730.
Conference:
2010 South East Nerve Net (SENN) and Georgia/South Carolina Neuroscience Consortium (GASCNC) conferences, Atlanta , United States, 5 Mar - 7 Mar, 2010.
Presentation Type:
Poster Presentation
Topic:
Posters
Citation:
Raz
L,
Zhang
QG,
Han
D,
Brann
DW,
Roffman
RC,
Weaver
AL and
Calabrese
RL
(2010). 17β-Estradiol Attenuates Proapoptotic p53/PUMA Signaling Pathway in Hippocampus CA1 following Global Ischemia.
Front. Neurosci.
Conference Abstract:
2010 South East Nerve Net (SENN) and Georgia/South Carolina Neuroscience Consortium (GASCNC) conferences.
doi: 10.3389/conf.fnins.2010.04.00073
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Received:
18 Mar 2010;
Published Online:
18 Mar 2010.
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Correspondence:
Limor Raz, Van der Veer Institute for Parkinson's and Brain Research, Institute of Molecular Medicine and Genetics, Developmental Neurobiology Program, Department of Neurology, Christchurch, United States, lraz@mcg.edu