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 conformational state of p53 in tissues from patients with Alzheimer's Disease (AD) that led to an impaired and dysfunctional response to stressors.


RESULTS
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
These results support the existence of a novel amyloid-based pathogenetic mechanism in AD potentially leading to the survival of injured dysfunctional cells.
Lanni
Cristina
C
Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy. cristina.lanni@unipv.it
Nardinocchi
Lavinia
L
Puca
Rosa
R
Stanga
Serena
S
Uberti
Daniela
D
Memo
Maurizio
M
Govoni
Stefano
S
D'Orazi
Gabriella
G
Racchi
Marco
M
D000544:Alzheimer Disease / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases