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Fe65 Ser228 is Phosphorylated by ATM/ATR and Inhibits Fe65-APP-Mediated Gene Transcription

Lookup NU author(s): Dr Paul Jowsey, Professor Peter Blain CBE

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Abstract

Fe65 binds the amyloid precursor protein (APP) and regulates the secretase-mediated processing of APP into several proteolytic fragments, including the amyloid-b (Ab) peptides and APP intracellular domain (AICD). Ab accumulation in neural plaques is a pathological feature of Alzheimer’s disease (AD) and AICD has important roles in the regulation of gene transcription (in complex with Fe65). It is therefore important to understand how Fe65 is regulated and how this contributes to the function and/or processing of APP. Studies have also implicated Fe65 in the cellular DNA damage response, with knockout mice showing increased DNA strand breaks and Fe65 demonstrating a gel mobility shift after DNA damage, consistent with protein phosphorylation. In this study, we identified Fe65 Ser228 as a novel target of the ATM and ATR protein kinases, in a reaction that occurred independently of APP. Neither phosphorylation nor mutation of Ser228 affected the Fe65-APP complex, though this was markedly decreased after UV treatment, with a concomitant decrease in the protein levels of APP in cells. Finally, mutation of Ser228 to Ala (thus blocking phosphorylation) caused a significant increase in Fe65-APP transcriptional activity, whereas phosphomimetic mutants (S228D and S228E) showed decreased transcriptional activity. These studies identify a novel phosphorylation site within Fe65 and a novel regulatory mechanism for the transcriptional activity of the Fe65-APP complex.


Publication metadata

Author(s): Jowsey PA, Blain PG

Publication type: Article

Publication status: Published

Journal: Biochemical Journal

Year: 2014

Online publication date: 14/11/2014

Acceptance date: 14/11/2014

ISSN (print): 0264-6021

ISSN (electronic): 1470-8728

Publisher: Portland Press Ltd.

URL: http://dx.doi.org/10.1042/BJ20140656

DOI: 10.1042/BJ20140656


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