Date Published: December 11, 2009
Publisher: Public Library of Science
Author(s): Thibaut Quillard, Julie Devalliere, Mathias Chatelais, Flora Coulon, Céline Séveno, Mathilde Romagnoli, Sophie Barillé Nion, Béatrice Charreau, Yihai Cao. http://doi.org/10.1371/journal.pone.0008244
Abstract: Notch signaling pathway controls key functions in vascular and endothelial cells (ECs) where Notch4 plays a major role. However, little is known about the contribution of other Notch receptors. This study investigated regulation of Notch2 and further examined its implication in EC dysfunction.
Partial Text: Notch signaling pathway regulates a broad array of cell fate decisions in various tissues and in all stages of development (embryonic to adult). The Notch family comprises heterodimer transmembrane receptors consisting of an extracellular domain and a noncovalently linked intracellular domain (ICD). In mammals, 4 Notch receptors (Notch1-4) and 5 ligands (Delta-like [Dll]-1, Dll3, Dll4, Jagged1 and Jagged2) have been identified . Upon interaction with ligands on neighbouring cells, Notch undergoes proteolytic cleavages managed sequentially by ADAM proteins (a desintegrin and metalloproteinase) and the γ-secretase complex. Release of the cytoplasmic Notch C-terminal intracellular domain (NICD) from the plasma membrane is followed by its translocation into the nucleus where it forms a complex with CSL, removing the repression and allowing for target genes (hes, hey) transcription .
Here, we provide evidence for a novel link between Notch and TNF signaling, where Notch2 is activated in response to TNF and directly controls expression of several genes involved in EC survival and apoptosis. Activation of Notch2 leads to a rapid decrease in survivin mRNA and protein expression, and survivin upregulation was obtained by the selective knockdown of Notch2 in ECs, indicating that survivin regulation is controlled at the Notch level.