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|Title:||Inhibition of Delta-induced Notch signaling using fucose analogs|
|Authors:||Haltiwanger, Robert S.|
Schneider, Michael Adam
Department of Molecular and Cellular Pharmacology.
Girnun, Geoffrey D.
Powers, Robert S.
|Abstract:||Notch is a cell surface receptor that controls cell fate decisions in metazoans. Notch signaling is regulated by O-glycans attached to epidermal growth factor-like (EGF) repeats in its extracellular domain. Protein O-fucosyltransferase 1 (POFUT1) is responsible for the addition of O-fucose to EGF repeats and is essential for Notch signaling. Constitutive activation of Notch is associated with a variety of human malignancies. Therefore, tools for the inhibition of Notch are being sought for the development of cancer therapeutics. Towards this end, we screened L-fucose analogs for their effects on Notch signaling. Treatment with 6-alkynyl and 6-alkenyl fucose reduced Notch ligand binding and Notch signaling induced by Notch ligands Dll1 and Dll4, but not Jag1. Inhibition was partially rescued by Fringe elongation of inhibitory fucose analogs. The inhibitory analogs effectively prevented Notch-dependent T-cell differentiation, inhibited glioma cell proliferation and inhibited Notch signaling in T-ALL associated Notch mutants. Additionally, we examined the role of O-fucosylation in a human patient’s congenital disorder resulting from a mutation in POFUT1, hepatocellular carcinoma, and regulation of a protein associated with Weill- Marchesani-like syndrome. Finally, we characterize the function of a novel O-glucose modification found on Notch EGF repeats.|
|Appears in Collections:||Stony Brook Theses and Dissertations Collection|
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