The amyloid precursor protein (APP) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism

Mi Li, Mariana Pehar, Yan Liu, Anita Bhattacharyya, Su Chun Zhang, Kenneth J. O'Riordan, Corinna Burger, Luciano D'Adamio, Luigi Puglielli

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2725-2736
Number of pages12
JournalNeurobiology of Aging
Volume36
Issue number10
DOIs
StatePublished - Oct 1 2015

Keywords

  • AICD
  • Aging
  • Alzheimer's disease
  • IRES
  • P44
  • P53

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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    Li, M., Pehar, M., Liu, Y., Bhattacharyya, A., Zhang, S. C., O'Riordan, K. J., Burger, C., D'Adamio, L., & Puglielli, L. (2015). The amyloid precursor protein (APP) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism. Neurobiology of Aging, 36(10), 2725-2736. https://doi.org/10.1016/j.neurobiolaging.2015.06.021