title: Zyxin is a novel target for β-amyloid peptide: characterization of its role in Alzheimer's pathogenesis.
abstract: Zyxin is an adaptor protein recently identified as a novel regulator of the homeodomain-interacting protein kinase 2 (HIPK2)-p53 signaling in response to DNA damage. We recently reported an altered conformational state of p53 in tissues from patients with Alzheimer 's disease (AD), because of a deregulation of HIPK2 activity, leading to an impaired and dysfunctional response to stressors. Here, we examined the molecular mechanisms underlying the deregulation of HIPK2 activity in two cellular models, HEK-293 cells and SH-SY5Y neuroblastoma cells differentiated with retinoic acid over-expressing the amyloid precursor protein, focusing on the evidence that zyxin expression is important to maintain HIPK2 protein stability. We demonstrated that both beta-amyloid (Aβ) 1-40 and 1-42 induce zyxin deregulation, thus affecting the transcriptional repressor activity of HIPK2 onto its target promoter, metallothionein 2A, which is in turn responsible for the induction of an altered conformational state of p53. We demonstrate for the first time that zyxin is a novel target of Aβ activities in AD. These results may help the studies on the pathogenesis of AD, through the fine dissection of events related to beta-amyloid activities.
authors: Department of Drug Sciences, Centre of Excellence in Applied Biology, University of Pavia, 27100 Pavia, Italy. cristina.lanni@unipv.it
authors: Cristina
authors: C
authors: Lanni
authors: Daniela
authors: D
authors: Necchi
authors: Antonella
authors: A
authors: Pinto
authors: Erica
authors: E
authors: Buoso
authors: Laura
authors: L
authors: Buizza
authors: Maurizio
authors: M
authors: Memo
authors: Daniela
authors: D
authors: Uberti
authors: Stefano
authors: S
authors: Govoni
authors: Marco
authors: M
authors: Racchi
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D010446:Peptide Fragments / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D055550:Protein Stability; D015398:Signal Transduction / Q000502:physiology; D060589:Zyxin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D010446:Peptide Fragments; D060589:Zyxin; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases