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The regulation of p53 up-regulated modulator of apoptosis by JNK/c-Jun pathway in β-amyloid-induced neuron death.
J Neurochem 2015; 134(6):1091-103JN

Abstract

Neuronal loss in selective areas of brain underlies the pathology of Alzheimer's disease (AD). Recent evidences place oligomeric β-amyloid (Aβ) central to the disease. However, mechanism of neuron death in response to Aβ remains elusive. Activation of the c-Jun N-terminal kinase (JNK) pathway and induction of the AP-1 transcription factor c-Jun are reported in AD. However, targets of JNK/c-Jun in Aβ-induced neuron death are mostly unknown. Our study shows that pro-apoptotic proteins, Bim (Bcl-2 interacting mediator of cell death) and Puma (p53 up-regulated modulator of apoptosis) are targets of c-Jun in Aβ-treated neurons. We demonstrate that the JNK/c-Jun pathway is activated, in cultures of cortical neurons following treatment with oligomeric Aβ and in AD transgenic mice, and that inhibition of this pathway by selective inhibitor blocks induction of Puma by Aβ. We also find that both JNK and p53 pathways co-operatively regulate Puma expression in Aβ-treated neurons. Moreover, we identified a novel AP1-binding site on rat puma gene which is necessary for direct binding of c-Jun with Puma promoter. Finally, we find that knocking down of c-Jun by siRNA provides significant protection from Aβ toxicity and that induction of Bim and Puma by Aβ in neurons requires c-Jun. Taken together, our results suggest that both Bim and Puma are target of c-Jun and elucidate the intricate regulation of Puma expression by JNK/c-Jun and p53 pathways in neurons upon Aβ toxicity. JNK/c-Jun pathway is shown to be activated in neurons of the Alzheimer's disease (AD) brain and plays a vital role in neuron death in AD models. However, downstream targets of c-Jun in this disease have not been thoroughly elucidated. Our study shows that two important pro-apoptotic proteins, Bim (Bcl-2 interacting mediator of cell death) and Puma (p53 up-regulated modulator of apoptosis) are targets of c-Jun in Aβ-treated neurons. We demonstrate that the JNK/c-jun pathway is activated, in cultures of cortical neurons following treatment with oligomeric Aβ and in AD transgenic mice, and that inhibition of this pathway by selective inhibitor blocks induction of Puma by Aβ. We have also observed functional co-operation of both JNK and p53 pathway in regulation of Puma under Aβ toxicity. Most importantly, we identified a novel AP1-binding site on rat puma gene which is necessary for direct binding of c-Jun with Puma promoter. Thus, our results suggest that both Bim and Puma are target of c-Jun and elucidate the intricate regulation of Puma expression by JNK/c-Jun and p53 pathways in neurons upon Aβ toxicity.

Authors+Show Affiliations

Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.

Pub Type(s)

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

Language

eng

PubMed ID

25891762

Citation

Akhter, Rumana, et al. "The Regulation of P53 Up-regulated Modulator of Apoptosis By JNK/c-Jun Pathway in Β-amyloid-induced Neuron Death." Journal of Neurochemistry, vol. 134, no. 6, 2015, pp. 1091-103.
Akhter R, Sanphui P, Das H, et al. The regulation of p53 up-regulated modulator of apoptosis by JNK/c-Jun pathway in β-amyloid-induced neuron death. J Neurochem. 2015;134(6):1091-103.
Akhter, R., Sanphui, P., Das, H., Saha, P., & Biswas, S. C. (2015). The regulation of p53 up-regulated modulator of apoptosis by JNK/c-Jun pathway in β-amyloid-induced neuron death. Journal of Neurochemistry, 134(6), pp. 1091-103. doi:10.1111/jnc.13128.
Akhter R, et al. The Regulation of P53 Up-regulated Modulator of Apoptosis By JNK/c-Jun Pathway in Β-amyloid-induced Neuron Death. J Neurochem. 2015;134(6):1091-103. PubMed PMID: 25891762.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The regulation of p53 up-regulated modulator of apoptosis by JNK/c-Jun pathway in β-amyloid-induced neuron death. AU - Akhter,Rumana, AU - Sanphui,Priyankar, AU - Das,Hrishita, AU - Saha,Pampa, AU - Biswas,Subhas Chandra, Y1 - 2015/04/28/ PY - 2014/11/27/received PY - 2015/03/10/revised PY - 2015/03/31/accepted PY - 2015/4/21/entrez PY - 2015/4/22/pubmed PY - 2015/12/15/medline KW - AP1 KW - Alzheimer's disease KW - JNK KW - Puma KW - c-Jun KW - β-amyloid SP - 1091 EP - 103 JF - Journal of neurochemistry JO - J. Neurochem. VL - 134 IS - 6 N2 - Neuronal loss in selective areas of brain underlies the pathology of Alzheimer's disease (AD). Recent evidences place oligomeric β-amyloid (Aβ) central to the disease. However, mechanism of neuron death in response to Aβ remains elusive. Activation of the c-Jun N-terminal kinase (JNK) pathway and induction of the AP-1 transcription factor c-Jun are reported in AD. However, targets of JNK/c-Jun in Aβ-induced neuron death are mostly unknown. Our study shows that pro-apoptotic proteins, Bim (Bcl-2 interacting mediator of cell death) and Puma (p53 up-regulated modulator of apoptosis) are targets of c-Jun in Aβ-treated neurons. We demonstrate that the JNK/c-Jun pathway is activated, in cultures of cortical neurons following treatment with oligomeric Aβ and in AD transgenic mice, and that inhibition of this pathway by selective inhibitor blocks induction of Puma by Aβ. We also find that both JNK and p53 pathways co-operatively regulate Puma expression in Aβ-treated neurons. Moreover, we identified a novel AP1-binding site on rat puma gene which is necessary for direct binding of c-Jun with Puma promoter. Finally, we find that knocking down of c-Jun by siRNA provides significant protection from Aβ toxicity and that induction of Bim and Puma by Aβ in neurons requires c-Jun. Taken together, our results suggest that both Bim and Puma are target of c-Jun and elucidate the intricate regulation of Puma expression by JNK/c-Jun and p53 pathways in neurons upon Aβ toxicity. JNK/c-Jun pathway is shown to be activated in neurons of the Alzheimer's disease (AD) brain and plays a vital role in neuron death in AD models. However, downstream targets of c-Jun in this disease have not been thoroughly elucidated. Our study shows that two important pro-apoptotic proteins, Bim (Bcl-2 interacting mediator of cell death) and Puma (p53 up-regulated modulator of apoptosis) are targets of c-Jun in Aβ-treated neurons. We demonstrate that the JNK/c-jun pathway is activated, in cultures of cortical neurons following treatment with oligomeric Aβ and in AD transgenic mice, and that inhibition of this pathway by selective inhibitor blocks induction of Puma by Aβ. We have also observed functional co-operation of both JNK and p53 pathway in regulation of Puma under Aβ toxicity. Most importantly, we identified a novel AP1-binding site on rat puma gene which is necessary for direct binding of c-Jun with Puma promoter. Thus, our results suggest that both Bim and Puma are target of c-Jun and elucidate the intricate regulation of Puma expression by JNK/c-Jun and p53 pathways in neurons upon Aβ toxicity. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/25891762/The_regulation_of_p53_up_regulated_modulator_of_apoptosis_by_JNK/c_Jun_pathway_in_β_amyloid_induced_neuron_death_ L2 - https://doi.org/10.1111/jnc.13128 DB - PRIME DP - Unbound Medicine ER -