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Glucocorticoid and growth factor synergism requirement for Notch4 chromatin domain activation.

Author	Jing Wu, Emery H Bresnick
Citation Information	Molecular and cellular biology, 27:2411-22 (2007)
Keywords	Animals, Base Sequence, Cell Line, Chromatin, Conserved Sequence, Glucocorticoids, Histones, Intercellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Receptors, Notch, Signal Transduction, Transcription Factor AP-1, Transcription, Genetic
Related Products	07-030
Pub Med ID	17220278

The Notch signaling pathway modulates cell fate in diverse contexts, including vascular development. Notch4 is selectively expressed in vascular endothelium and regulates vascular remodeling. The signal-dependent transcription factor activator protein 1 (AP-1) activates Notch4 transcription in endothelial cells, but other factors/signals that regulate Notch4 are largely unknown. We demonstrate that, unlike the established transrepression mechanism in which the glucocorticoid receptor (GR) antagonizes AP-1, AP-1 and GR synergistically activated Notch4 transcription in endothelial cells. Fibroblast growth factor 2 (FGF-2) and cortisol induced AP-1 and GR occupancy, respectively, at a Notch4 promoter composite response element consisting of an imperfect half-glucocorticoid response element and an AP-1 motif, which mediated signal-dependent activation. Analysis of Notch4 promoter complex assembly provided evidence that GR and AP-1 independently occupy the composite response element, but AP-1 stabilizes GR occupancy. In multipotent 10T1/2 cells, FGF-2 and cortisol induced a histone modification pattern at the Notch4 locus mimicking that present in endothelial cells and reprogrammed Notch4 from a repressed to an active state. These results establish the molecular basis for a novel AP-1/GR-Notch4 axis in vascular endothelium.