title: The essential role of p53-up-regulated modulator of apoptosis (Puma) and its regulation by FoxO3a transcription factor in β-amyloid-induced neuron death.
abstract: Neurodegeneration underlies the pathology of Alzheimer disease (AD). The molecules responsible for such neurodegeneration in AD brain are mostly unknown. Recent findings indicate that the BH3-only proteins of the Bcl-2 family play an essential role in various cell death paradigms, including neurodegeneration. Here we report that Puma (p53-up-regulated modulator of apoptosis), an important member of the BH3-only protein family, is up-regulated in neurons upon toxic β-amyloid 1-42 (Aβ(1-42)) exposure both in vitro and in vivo. Down-regulation of Puma by specific siRNA provides significant protection against neuron death induced by Aβ(1-42). We further demonstrate that the activation of p53 and inhibition of PI3K/Akt pathways induce Puma. The transcription factor FoxO3a, which is activated when PI3K/Akt signaling is inhibited, directly binds with the Puma gene and induces its expression upon exposure of neurons to oligomeric Aβ(1-42). Moreover, Puma cooperates with another BH3-only protein, Bim, which is already implicated in AD. Our results thus suggest that Puma is activated by both p53 and PI3K/Akt/FoxO3a pathways and cooperates with Bim to induce neuron death in response to Aβ(1-42).
authors.affiliation: Cell Biology and Physiology Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
authors.forename: Rumana
authors.initials: R
authors.lastname: Akhter
authors.affiliation: Cell Biology and Physiology Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
authors.forename: Priyankar
authors.initials: P
authors.lastname: Sanphui
authors.affiliation: Cell Biology and Physiology Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India. Electronic address: biswassc@gmail.com.
authors.forename: Subhas Chandra
authors.initials: SC
authors.lastname: Biswas
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D016923:Cell Death; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D008297:Male; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C533952:Bbc3 protein, rat; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer Disease; Amyloid; Bcl-2 Family Proteins; Bim; Cell Death; Foxo; Neurodegeneration; Neurons; Puma; siRNA