Zyxin is a novel target for β-amyloid peptide: characterization of its role in Alzheimer's pathogenesis
| Autor: | Daniela Necchi, Maurizio Memo, Erica Buoso, Daniela Uberti, Antonella Pinto, Cristina Lanni, Stefano Govoni, Laura Buizza, Marco Racchi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Amyloid
DNA damage Cell Survival Regulator Retinoic acid Protein Serine-Threonine Kinases Biochemistry Zyxin Cell Line methods antagonists /&/ inhibitors/metabolism Cellular and Molecular Neuroscience chemistry.chemical_compound Drug Delivery Systems Alzheimer Disease Cell Line Tumor Amyloid precursor protein Humans Protein kinase A administration /&/ dosage Amyloid beta-Peptides antagonists /&/ inhibitors/physiology Tumor biology Protein Stability Signal transducing adaptor protein Protein-Serine-Threonine Kinases Peptide Fragments drug effects/physiology HEK293 Cells chemistry physiology biology.protein Cancer research etiology/metabolism/pathology Amyloid beta-Peptides administration /&/ dosage Carrier Proteins antagonists /&/ inhibitors/physiology Cell Line Tumor Cell Survival drug effects/physiology Drug Delivery Systems methods HEK293 Cells Humans Peptide Fragments administration /&/ dosage Protein Stability Protein-Serine-Threonine Kinases antagonists /&/ inhibitors/physiology Signal Transduction physiology Zyxin etiology/metabolism/pathology Carrier Proteins Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|