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.