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

PLoS One. 2010 Apr 14;5(4):e10171. doi: 10.1371/journal.pone.0010171.

Abstract

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-1alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor
  • Carrier Proteins / metabolism*
  • Carrier Proteins / physiology
  • Cell Survival
  • Cells, Cultured
  • DNA / metabolism
  • Humans
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Folding
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / physiology
  • Tumor Suppressor Protein p53 / chemistry*

Substances

  • Amyloid beta-Protein Precursor
  • Carrier Proteins
  • Tumor Suppressor Protein p53
  • DNA
  • HIPK2 protein, human
  • Protein-Serine-Threonine Kinases