P44, the ‘longevity-assurance’ isoform of P53, regulates tau phosphorylation and is activated in an age-dependent fashion
| Autor: | Mi Hee Ko, Mi Li, Mariana Pehar, Heidi Scrable, Luigi Puglielli |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Genetically modified mouse
p53 endocrine system DYRK1A Tau protein Mice Transgenic tau Proteins Biology environment and public health Mice Alzheimer Disease parasitic diseases Animals Protein Isoforms tau Cognitive decline Phosphorylation p44 Kinase Cyclin-dependent kinase 5 aging Age Factors Cell Biology Original Articles cognitive decline Molecular biology Peptide Fragments enzymes and coenzymes (carbohydrates) biology.protein Signal transduction biological phenomena cell phenomena and immunity Tumor Suppressor Protein p53 Alzheimer’s disease Signal Transduction Transcription Factors |
| Zdroj: | Aging Cell |
| ISSN: | 1474-9726 1474-9718 |
| Popis: | 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, GSK3β, 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. |
| Databáze: | OpenAIRE |
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