title: The regulation of p53 up-regulated modulator of apoptosis by JNK/c-Jun pathway in β-amyloid-induced neuron death.
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.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Rumana
authors.initials: R
authors.lastname: Akhter
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Priyankar
authors.initials: P
authors.lastname: Sanphui
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Hrishita
authors.initials: H
authors.lastname: Das
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Pampa
authors.initials: P
authors.lastname: Saha
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Subhas Chandra
authors.initials: SC
authors.lastname: Biswas
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology*; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C533952:Bbc3 protein, rat; C488588:PUMA protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
keywords: AP1; Alzheimer's disease; JNK; Puma; c-Jun; β-amyloid