title: P44, the 'longevity-assurance' isoform of P53, regulates tau phosphorylation and is activated in an age-dependent fashion.
abstract: 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.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, 2500 Overlook Terrace, Madison, WI, 53705, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Pehar
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Ko
authors.forename: Mi
authors.initials: M
authors.lastname: Li
authors.forename: Heidi
authors.initials: H
authors.lastname: Scrable
authors.forename: Luigi
authors.initials: L
authors.lastname: Puglielli
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms; D015398:Signal Transduction; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D020033:Protein Isoforms; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C503486:WDR77 protein, mouse; D016875:tau Proteins
keywords: Alzheimer's disease; aging; cognitive decline; p44; p53; tau