title: The amyloid precursor protein (APP) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism.
abstract: p44 is a short isoform of the tumor suppressor protein p53 that is regulated in an age-dependent manner. When overexpressed in the mouse, it causes a progeroid phenotype that includes premature cognitive decline, synaptic defects, and hyperphosphorylation of tau. The hyperphosphorylation of tau has recently been linked to the ability of p44 to regulate transcription of relevant tau kinases. Here, we report that the amyloid precursor protein (APP) intracellular domain (AICD), which results from the processing of the APP, regulates translation of p44 through a cap-independent mechanism that requires direct binding to the second internal ribosome entry site (IRES) of the p53 mRNA. We also report that AICD associates with nucleolin, an already known IRES-specific trans-acting factor that binds with p53 IRES elements and regulates translation of p53 isoforms. The potential biological impact of our findings was assessed in a mouse model of Alzheimer's disease. In conclusion, our study reveals a novel aspect of AICD and p53/p44 biology and provides a possible molecular link between APP, p44, and tau.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Mi
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Pehar
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Bhattacharyya
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Su-Chun
authors.initials: SC
authors.lastname: Zhang
authors.affiliation: Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Riordan
authors.affiliation: Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Corinna
authors.initials: C
authors.lastname: Burger
authors.affiliation: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, USA; Geriatric Research Education Clinical Center, VA Medical Center, Madison, WI, USA; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA. Electronic address: lp1@medicine.wisc.edu.
authors.forename: Luigi
authors.initials: L
authors.lastname: Puglielli
mesh_terms: D000375:Aging / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000235:genetics*; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000235:genetics*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D000067556:Internal Ribosome Entry Sites; D010446:Peptide Fragments; D012333:RNA, Messenger; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C478359:WDR77 protein, human; C503486:WDR77 protein, mouse; D016875:tau Proteins
keywords: AICD; Aging; Alzheimer's disease; IRES; p44; p53