TY - JOUR
T1 - The amyloid precursor protein (APP) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism
AU - Li, Mi
AU - Pehar, Mariana
AU - Liu, Yan
AU - Bhattacharyya, Anita
AU - Zhang, Su Chun
AU - O'Riordan, Kenneth J.
AU - Burger, Corinna
AU - D'Adamio, Luciano
AU - Puglielli, Luigi
N1 - Funding Information:
The authors wish to remember Dr Heidi Scrable, who died on February 13, 2013, after a prolonged battle with a disease. Although she participated in all intellectual aspects of this work, she never saw the final version of this manuscript. The authors thank Dr Robin Fahraeus for the bicistronic construct. This work was supported by VA Merit Award (BX001638), NIH ( P50 AG033514 and GM103542 ), and Thome Memorial Foundation .
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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.
KW - AICD
KW - Aging
KW - Alzheimer's disease
KW - IRES
KW - P44
KW - P53
UR - http://www.scopus.com/inward/record.url?scp=84940960828&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84940960828&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2015.06.021
DO - 10.1016/j.neurobiolaging.2015.06.021
M3 - Article
C2 - 26174856
AN - SCOPUS:84940960828
SN - 0197-4580
VL - 36
SP - 2725
EP - 2736
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 10
ER -