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

NEUROBIOLOGY OF AGING

卷:36

Article

Li, Mi¹  Pehar, Mariana¹  Liu, Yan²  Bhattacharyya, Anita²  Zhang, Su-Chun^2,3  O'Riordan, Kenneth J.⁴  Burger, Corinna⁴  D'Adamio, Luciano⁵  Puglielli, Luigi^1,3,6,7 

[1] Univ Wisconsin, Dept Med, Madison, WI 53705 USA

[2] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA

[3] Univ Wisconsin, Dept Neurosci, Madison, WI 53705 USA

[4] Univ Wisconsin, Dept Neurol, Madison, WI 53705 USA

[5] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA

[6] VA Med Ctr, Geriatr Res Educ Clin Ctr, Madison, WI USA

[7] Univ Wisconsin, Wisconsin Alzheimers Dis Res Ctr, Madison, WI 53705 USA

关键词: p53;    p44;    AICD;    IRES;    Aging;    Alzheimer's disease;   

DOI  :  10.1016/j.neurobiolaging.2015.06.021

来源: Elsevier

【 摘 要 】

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. (C) 2015 Elsevier Inc. All rights reserved.

【 授权许可】

Free