A Switch in @entity584 Isoforms Is Required for Notch-Induced XXXX Expression and Protection from Cell Death.

@entity4245 @entity3545 @entity72699 @entity584 @entity3546 @entity2533 @entity4012 @entity23698 @entity9459 @entity15914
Notch activation in aortic endothelial cells (ECs) takes place at embryonic stages during cardiac valve formation and induces endothelial-to-mesenchymal transition (EndMT). Using aortic ECs, we show here that active Notch expression promotes EndMT, resulting in downregulation of @entity3545 ( @entity3545 ) and upregulation of mesenchymal genes such as those for fibronectin and @entity72699 . In these cells, @entity2533 exacerbates Notch effects by increasing @entity4245 and fibronectin activation. When Notch-downstream pathways were analyzed, we detected an increase in @entity9459 ( @entity9459 ) phosphorylation and inactivation that facilitates @entity4245 nuclear retention and protein stabilization. However, the total activity of @entity584 was downregulated. The discrepancy between @entity584 activity and @entity9459 phosphorylation is explained by a Notch-induced switch in the @entity584 isoforms, whereby @entity584 , the predominant isoform expressed in ECs, is decreased and @entity23698 transcription is upregulated. Mechanistically, @entity23698 induction requires the stimulation of the @entity3546 / @entity15914 transcriptional complex, which activates the @entity23698 promoter. Active, phosphorylated @entity23698 translocates to the nucleus in Notch-expressing cells, resulting in @entity9459 inactivation in this compartment. @entity23698 , but not @entity584 , colocalizes in the nucleus with lamin B in the nuclear envelope. In addition to promoting @entity9459 inactivation, Notch downregulates @entity4012 ( @entity4012 ), another @entity23698 nuclear substrate. Moreover, Notch protects ECs from oxidative stress-induced apoptosis through an @entity23698 - and @entity4245 -dependent mechanism.
