Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic–Ischemic Brain Damage in Neonatal Rats

c-Jun N-terminal kinase (JNK) plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal...

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Main Authors:	Li, Deyuan, Li, Xihong, Wu, Jinlin, Li, Jinhui, Zhang, Li, Xiong, Tao, Tang, Jun, Qu, Yi, Mu, Dezhi
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501737/

id	pubmed-4501737
recordtype	oai_dc
spelling	pubmed-45017372015-07-17 Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic–Ischemic Brain Damage in Neonatal Rats Li, Deyuan Li, Xihong Wu, Jinlin Li, Jinhui Zhang, Li Xiong, Tao Tang, Jun Qu, Yi Mu, Dezhi Research Article c-Jun N-terminal kinase (JNK) plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI). In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage. Public Library of Science 2015-07-14 /pmc/articles/PMC4501737/ /pubmed/26171786 http://dx.doi.org/10.1371/journal.pone.0132998 Text en © 2015 Li et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Li, Deyuan Li, Xihong Wu, Jinlin Li, Jinhui Zhang, Li Xiong, Tao Tang, Jun Qu, Yi Mu, Dezhi
spellingShingle	Li, Deyuan Li, Xihong Wu, Jinlin Li, Jinhui Zhang, Li Xiong, Tao Tang, Jun Qu, Yi Mu, Dezhi Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic–Ischemic Brain Damage in Neonatal Rats
author_facet	Li, Deyuan Li, Xihong Wu, Jinlin Li, Jinhui Zhang, Li Xiong, Tao Tang, Jun Qu, Yi Mu, Dezhi
author_sort	Li, Deyuan
title	Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic–Ischemic Brain Damage in Neonatal Rats
title_short	Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic–Ischemic Brain Damage in Neonatal Rats
title_full	Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic–Ischemic Brain Damage in Neonatal Rats
title_fullStr	Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic–Ischemic Brain Damage in Neonatal Rats
title_full_unstemmed	Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic–Ischemic Brain Damage in Neonatal Rats
title_sort	involvement of the jnk/foxo3a/bim pathway in neuronal apoptosis after hypoxic–ischemic brain damage in neonatal rats
description	c-Jun N-terminal kinase (JNK) plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI). In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501737/
_version_	1613247712805781504

Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic–Ischemic Brain Damage in Neonatal Rats

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