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The oligomeric complexes involving FE65 and APP control cell cycle progression through the transcriptional regulation of thymidilate synthase gene
The functions of the oligomeric complexes that include the Alzheimer’s
beta-amyloid precursor protein (APP) and the adaptor protein Fe65 are still
unknown. We demonstrated that Fe65 is present both in the cytoplasm and
in the nucleus and that APP functions as an extranuclear anchor, which prevents
Fe65 nuclear translocation. This suggests the hypothesis that, similar
to what was observed for Notch, the presenilin-mediated cleavage of APP
could result in the translocation of Fe65 to the nucleus and, in turn, in the
regulation of transcription or of other nuclear functions. According to this
hypothesis, we and others demonstrated that Fe65 could play a role in the
regulation of transcription. We are addressing this hypothesis, and several
lines of evidence support it. First, we have demonstrated that the overexpression
of Fe65 affects cell cycle progression by inhibiting the expression of the
thymidylate synthase (TS), a key enzyme of the S phase of cell cycle. This
inhibition is observed only when overexpressed Fe65 accumulates in the nucleus
and several results suggest that it is the consequence of a Fe65-mediated
regulation of the TS gene. Second, Fe65 has three protein–protein interaction
domains, a PTB domain interacting with APP, a second PTB domain,
which binds to two nuclear proteins, the transcription factor LSF or to the
histone acetylase Tip60.We have now identified numerous possible ligands
of the third domain of Fe65, theWWdomain, and many of these molecules
are nuclear proteins. Third, when the WW domain is fused to a DNA binding
domain of a transcription factor, the fusion protein is able to regulate
the transcription of a reporter gene. The involvement of Fe65–APP complex
in the regulation of gene expression could have a significant impact
on understanding of the molecular basis of Alzheimer’s disease: in fact, the
increased beta–gamma-processing of APP could be accompanied by an increased
Fe65 nuclear translocation and, in turn, by an alteration of nuclear
functions