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The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia.
J Neurosci 2004; 24(36):7879-87JN

Abstract

The c-Jun N-terminal protein kinase (JNK) signaling pathway is implicated in neuronal apoptosis. The mechanism by which activated JNK induces neuronal apoptosis is strongly linked to mitochondrial apoptogenic proteins, although the molecular machinery downstream of JNK has not been precisely elucidated. Our study examined the relevance of proapoptotic Bcl-2 family members in JNK-mediated apoptosis after transient focal cerebral ischemia (tFCI), which, when induced by 60 min of middle cerebral artery (MCA) occlusion, elevated levels of JNK activity and phospho-JNK in the MCA territory. Phospho-JNK was primarily expressed in neurons and colocalized with terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-positive cells. Inhibition of JNK activity by anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), a selective JNK inhibitor, protected neurons from ischemia-induced apoptosis detected by TUNEL staining and an apoptotic-related DNA fragmentation assay. SP600125 blocked translocation of the cell death effector Bax from the cytosol to the mitochondria after tFCI. BimL (Bim long) was induced and phosphorylated parallel to JNK activity. Coimmunoprecipitation studies consistently revealed increased interaction of JNK with BimL, as well as BimL with Bax, after tFCI. SP600125 blocked these interactions at a dose that significantly inhibited JNK-induced neuronal apoptosis. These results suggest that the JNK signaling pathway is involved in ischemia-induced neuronal apoptosis by stimulation, at least in part, of Bax translocation to the mitochondria, in which BimL is likely regulated by JNK as a downstream substrate for transmission of apoptotic signals to Bax.

Authors+Show Affiliations

Department of Neurosurgery, Program in Neurosciences, Stanford University School of Medicine, Stanford, California 94305-5487, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15356200

Citation

Okuno, Shuzo, et al. "The c-Jun N-terminal Protein Kinase Signaling Pathway Mediates Bax Activation and Subsequent Neuronal Apoptosis Through Interaction With Bim After Transient Focal Cerebral Ischemia." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 24, no. 36, 2004, pp. 7879-87.
Okuno S, Saito A, Hayashi T, et al. The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci. 2004;24(36):7879-87.
Okuno, S., Saito, A., Hayashi, T., & Chan, P. H. (2004). The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 24(36), pp. 7879-87.
Okuno S, et al. The c-Jun N-terminal Protein Kinase Signaling Pathway Mediates Bax Activation and Subsequent Neuronal Apoptosis Through Interaction With Bim After Transient Focal Cerebral Ischemia. J Neurosci. 2004 Sep 8;24(36):7879-87. PubMed PMID: 15356200.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. AU - Okuno,Shuzo, AU - Saito,Atsushi, AU - Hayashi,Takeshi, AU - Chan,Pak H, PY - 2004/9/10/pubmed PY - 2005/4/6/medline PY - 2004/9/10/entrez SP - 7879 EP - 87 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 24 IS - 36 N2 - The c-Jun N-terminal protein kinase (JNK) signaling pathway is implicated in neuronal apoptosis. The mechanism by which activated JNK induces neuronal apoptosis is strongly linked to mitochondrial apoptogenic proteins, although the molecular machinery downstream of JNK has not been precisely elucidated. Our study examined the relevance of proapoptotic Bcl-2 family members in JNK-mediated apoptosis after transient focal cerebral ischemia (tFCI), which, when induced by 60 min of middle cerebral artery (MCA) occlusion, elevated levels of JNK activity and phospho-JNK in the MCA territory. Phospho-JNK was primarily expressed in neurons and colocalized with terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-positive cells. Inhibition of JNK activity by anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), a selective JNK inhibitor, protected neurons from ischemia-induced apoptosis detected by TUNEL staining and an apoptotic-related DNA fragmentation assay. SP600125 blocked translocation of the cell death effector Bax from the cytosol to the mitochondria after tFCI. BimL (Bim long) was induced and phosphorylated parallel to JNK activity. Coimmunoprecipitation studies consistently revealed increased interaction of JNK with BimL, as well as BimL with Bax, after tFCI. SP600125 blocked these interactions at a dose that significantly inhibited JNK-induced neuronal apoptosis. These results suggest that the JNK signaling pathway is involved in ischemia-induced neuronal apoptosis by stimulation, at least in part, of Bax translocation to the mitochondria, in which BimL is likely regulated by JNK as a downstream substrate for transmission of apoptotic signals to Bax. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/15356200/The_c_Jun_N_terminal_protein_kinase_signaling_pathway_mediates_Bax_activation_and_subsequent_neuronal_apoptosis_through_interaction_with_Bim_after_transient_focal_cerebral_ischemia_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=15356200 DB - PRIME DP - Unbound Medicine ER -