Homeodomain interacting protein kinase 2: a target for Alzheimer's beta amyloid leading to misfolded p53 and inappropriate cell survival.

<h4>Background</h4>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...

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Autores principales:	Cristina Lanni, Lavinia Nardinocchi, Rosa Puca, Serena Stanga, Daniela Uberti, Maurizio Memo, Stefano Govoni, Gabriella D'Orazi, Marco Racchi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dff16ab6748641c79065b852b6e8ba51
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spelling	oai:doaj.org-article:dff16ab6748641c79065b852b6e8ba512021-11-25T06:24:33ZHomeodomain interacting protein kinase 2: a target for Alzheimer's beta amyloid leading to misfolded p53 and inappropriate cell survival.1932-620310.1371/journal.pone.0010171https://doaj.org/article/dff16ab6748641c79065b852b6e8ba512010-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20418953/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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-1alpha and metallothionein 2A.<h4>Conclusions/significance</h4>These results support the existence of a novel amyloid-based pathogenetic mechanism in AD potentially leading to the survival of injured dysfunctional cells.Cristina LanniLavinia NardinocchiRosa PucaSerena StangaDaniela UbertiMaurizio MemoStefano GovoniGabriella D'OraziMarco RacchiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 4, p e10171 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cristina Lanni Lavinia Nardinocchi Rosa Puca Serena Stanga Daniela Uberti Maurizio Memo Stefano Govoni Gabriella D'Orazi Marco Racchi Homeodomain interacting protein kinase 2: a target for Alzheimer's beta amyloid leading to misfolded p53 and inappropriate cell survival.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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-1alpha and metallothionein 2A.<h4>Conclusions/significance</h4>These results support the existence of a novel amyloid-based pathogenetic mechanism in AD potentially leading to the survival of injured dysfunctional cells.
format	article
author	Cristina Lanni Lavinia Nardinocchi Rosa Puca Serena Stanga Daniela Uberti Maurizio Memo Stefano Govoni Gabriella D'Orazi Marco Racchi
author_facet	Cristina Lanni Lavinia Nardinocchi Rosa Puca Serena Stanga Daniela Uberti Maurizio Memo Stefano Govoni Gabriella D'Orazi Marco Racchi
author_sort	Cristina Lanni
title	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_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_sort	homeodomain interacting protein kinase 2: a target for alzheimer's beta amyloid leading to misfolded p53 and inappropriate cell survival.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/dff16ab6748641c79065b852b6e8ba51
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Homeodomain interacting protein kinase 2: a target for Alzheimer's beta amyloid leading to misfolded p53 and inappropriate cell survival.

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