title: BAG2 Is Repressed by NF-κB Signaling, and Its Overexpression Is Sufficient to Shift Aβ1-42 from Neurotrophic to Neurotoxic in Undifferentiated SH-SY5Y Neuroblastoma.
abstract: Amyloid-beta (Aβ) binds to various neuronal receptors and elicits a context- and dose-dependent toxic or trophic response from neurons. The molecular mechanisms for this phenomenon are presently unknown. The cochaperone BAG2 has been shown to mediate important cellular responses to stress, including cell cycle arrest and apoptosis. Here, we use SH-SY5Y neuroblastoma cells to characterize BAG2 expression and regulation and investigate the involvement of BAG2 in Aβ1-42-mediated neurotrophism or neurotoxicity in the context of differentiation. We report that BAG2 is upregulated on differentiation of SH-SY5Y cells into neuron-like cells. This increase in BAG2 expression is accompanied by a change in response to treatment with Aβ1-42 from neurotrophic to neurotoxic. Further, overexpression of BAG2 in undifferentiated SH-SY5Y cells was sufficient to induce the change from neurotrophic to neurotoxic response. Of several transcription factors queried, the putative BAG2 promoter had a higher-than-expected occurrence of response elements (RE) for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Treatment with JSH-23, a potent inhibitor of NF-κB, caused a marked increase in BAG2 mRNA expression, suggesting that NF-κB is a repressor of BAG2 transcription in undifferentiated SH-SY5Y cells. Together, these data suggest that NF-κB-mediated modulation of BAG2 expression constitutes a "switch" that regulates the shift between the neurotrophic and neurotoxic effects of Aβ1-42.
authors.affiliation: Pós-graduação em Neurociência e Cognição, Universidade Federal do ABC, São Bernardo do Campo, Brazil, fernando.santiago@ufabc.edu.br.
authors.forename: Fernando E
authors.initials: FE
authors.lastname: Santiago
authors.forename: Maria Camila
authors.initials: MC
authors.lastname: Almeida
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Carrettiero
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity*; D020218:Response Elements; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; C492980:BAG2 protein, human; D018832:Molecular Chaperones; D016328:NF-kappa B; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)