Open AccessP44, the ‘longevity‐assurance’ isoform of P53, regulates tau phosphorylation and is activated in an age‐dependent fashion
Author(s) -
Pehar Mariana,
Ko Mi Hee,
Li Mi,
Scrable Heidi,
Puglielli Luigi
Publication year - 2014
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12192
Subject(s) - phosphorylation , biology , gene isoform , cyclin dependent kinase 5 , kinase , phenotype , microbiology and biotechnology , transgene , genetically modified mouse , transcription factor , downregulation and upregulation , dyrk1a , protein kinase a , genetics , gene , cyclin dependent kinase 2
Summary p44 is a short isoform of p53 with ‘longevity‐assurance’ activity. Overexpression of p44 in the mouse (p44 +/+ transgenic mice) causes a progeroid phenotype that mimics an accelerated form of aging. The phenotype includes abnormal phosphorylation of the microtubule‐binding protein tau, synaptic deficits, and cognitive decline. Genetic engineering demonstrated that the phosphorylation status of tau acts upstream of the synaptic deficits. Here, we provide evidence that p44 promotes the phosphorylation of tau in the mouse. Specifically, we show that p44 binds to the promoter of tau kinases Dyrk1A, GSK 3β, Cdk5, p35, and p39 and activates their transcription. The upregulation of the above kinases is followed by increased phosphorylation of tau. Finally, we show that p44 is preferentially found in the nucleus and that its levels increase with age in the mouse brain. Taken together, these results suggest that an imbalance in the p53:p44 ratio might be involved with the altered tau metabolism that characterizes aging.