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First published online August 26, 2004

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Signalling by secretase

Amyloid precursor protein (APP), a single-pass transmembrane protein, is often seen as a `bad guy' because of its sequential proteolytic conversion by secretases, including -secretase, into ß-amyloid peptides, which form plaques in the brains of patients with Alzheimer's disease. However, -secretase activity also generates APP intracellular domain (AICD) from APP, and Uwe Konietzko and colleagues now describe a physiological role for AICD in nuclear signalling (see p. 4435). The authors use inducible expression of a fluorescently tagged AICD together with co-transfection of the APP adaptor proteins Fe65, Jip1b, X11a(MINT1) and the chromatin-associated protein Tip60 to analyze AICD's nuclear signalling function. Fe65 and Jip1b independently transport AICD into the nucleus and dock it with Tip60 but X11a(MINT1) traps AICD in the cytoplasm. While AICD-Fe65-Tip60 complexes concentrate in spherical nuclear spots, AICD-Jip1b-Tip60 complexes form speckled structures. Finally, AICD upregulates the expression of APP and of several genes whose products are involved in its processing and cellular function. Given these activities of AICD and -secretase's involvement in the Notch and other nuclear signalling pathways, the therapeutic use of -secretase inhibitors must be carefully evaluated, conclude the authors.

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The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor

Ruth C. von Rotz, Bernhard M. Kohli, Jérôme Bosset, Michelle Meier, Toshiharu Suzuki, Roger M. Nitsch, and Uwe Konietzko
JCS 2004 117: 4435-4448. [Abstract] [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content