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Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival

BACKGROUND: Homeodomain interacting protein kinase 2 (HIPK2) is an evolutionary conserved serine/threonine kinase whose activity is fundamental in maintaining wild-type p53 function, thereby controlling the destiny of cells when exposed to DNA damaging agents. We recently reported an altered conform...

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Autores principales: Lanni, Cristina, Nardinocchi, Lavinia, Puca, Rosa, Stanga, Serena, Uberti, Daniela, Memo, Maurizio, Govoni, Stefano, D'Orazi, Gabriella, Racchi, Marco
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854690/
https://www.ncbi.nlm.nih.gov/pubmed/20418953
http://dx.doi.org/10.1371/journal.pone.0010171
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author Lanni, Cristina
Nardinocchi, Lavinia
Puca, Rosa
Stanga, Serena
Uberti, Daniela
Memo, Maurizio
Govoni, Stefano
D'Orazi, Gabriella
Racchi, Marco
author_facet Lanni, Cristina
Nardinocchi, Lavinia
Puca, Rosa
Stanga, Serena
Uberti, Daniela
Memo, Maurizio
Govoni, Stefano
D'Orazi, Gabriella
Racchi, Marco
author_sort Lanni, Cristina
collection PubMed
description BACKGROUND: Homeodomain interacting protein kinase 2 (HIPK2) is an evolutionary conserved serine/threonine kinase whose activity is fundamental in maintaining wild-type p53 function, thereby controlling the destiny of cells when exposed to DNA damaging agents. We recently reported an altered conformational state of p53 in tissues from patients with Alzheimer's Disease (AD) that led to an impaired and dysfunctional response to stressors. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined the molecular mechanisms underlying the impairment of p53 activity in two cellular models, HEK-293 cells overexpressing the amyloid precursor protein and fibroblasts from AD patients, starting from recent findings showing that p53 conformation may be regulated by HIPK2. We demonstrated that beta-amyloid 1–40 induces HIPK2 degradation and alters HIPK2 binding activity to DNA, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus. Expression of HIPK2 was analysed by western blot experiments, whereas HIPK2 DNA binding was examined by chromatin immunoprecipitation analysis. In particular, we evaluated the recruitment of HIPK2 onto some target promoters, including hypoxia inducible factor-1α and metallothionein 2A. CONCLUSIONS/SIGNIFICANCE: These results support the existence of a novel amyloid-based pathogenetic mechanism in AD potentially leading to the survival of injured dysfunctional cells.
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spelling pubmed-28546902010-04-23 Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival Lanni, Cristina Nardinocchi, Lavinia Puca, Rosa Stanga, Serena Uberti, Daniela Memo, Maurizio Govoni, Stefano D'Orazi, Gabriella Racchi, Marco PLoS One Research Article BACKGROUND: Homeodomain interacting protein kinase 2 (HIPK2) is an evolutionary conserved serine/threonine kinase whose activity is fundamental in maintaining wild-type p53 function, thereby controlling the destiny of cells when exposed to DNA damaging agents. We recently reported an altered conformational state of p53 in tissues from patients with Alzheimer's Disease (AD) that led to an impaired and dysfunctional response to stressors. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined the molecular mechanisms underlying the impairment of p53 activity in two cellular models, HEK-293 cells overexpressing the amyloid precursor protein and fibroblasts from AD patients, starting from recent findings showing that p53 conformation may be regulated by HIPK2. We demonstrated that beta-amyloid 1–40 induces HIPK2 degradation and alters HIPK2 binding activity to DNA, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus. Expression of HIPK2 was analysed by western blot experiments, whereas HIPK2 DNA binding was examined by chromatin immunoprecipitation analysis. In particular, we evaluated the recruitment of HIPK2 onto some target promoters, including hypoxia inducible factor-1α and metallothionein 2A. CONCLUSIONS/SIGNIFICANCE: These results support the existence of a novel amyloid-based pathogenetic mechanism in AD potentially leading to the survival of injured dysfunctional cells. Public Library of Science 2010-04-14 /pmc/articles/PMC2854690/ /pubmed/20418953 http://dx.doi.org/10.1371/journal.pone.0010171 Text en Lanni et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lanni, Cristina
Nardinocchi, Lavinia
Puca, Rosa
Stanga, Serena
Uberti, Daniela
Memo, Maurizio
Govoni, Stefano
D'Orazi, Gabriella
Racchi, Marco
Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival
title Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival
title_full Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival
title_fullStr Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival
title_full_unstemmed Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival
title_short Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival
title_sort homeodomain interacting protein kinase 2: a target for alzheimer's beta amyloid leading to misfolded p53 and inappropriate cell survival
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854690/
https://www.ncbi.nlm.nih.gov/pubmed/20418953
http://dx.doi.org/10.1371/journal.pone.0010171
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