%0 PDF %T Proteasome and VCP inhibition blocks necroptosis in HT-29 cells %A Gurol, Kerem. %D 2018-09-11T11:06:04.913-04:00 %8 2018-09-11 %R http://localhost/files/n009wd53w %X Abstract: Necroptosis is a programmed form of cell death mediated by the formation of a detergent-insoluble protein complex called necrosome. Receptor Interacting Protein Kinases (RIPK) 1 and 3 have been identified as the key components of the necrosome. Phosphorylation and ubiquitination of several RIPK1/3 residues have been implicated to play important roles in regulating apoptosis and necroptosis. As the main mechanism for cellular protein degradation, ubiquitin-proteasome system (UPS) has been associated with a myriad of cellular pathways, including apoptosis. However, the mechanism and function of UPS under apoptotic or necroptotic conditions are poorly understood. Here we report that proteasome inhibitor bortezomib and Valosin-Containing Protein (VCP) inhibitor NMS-873 inhibit necroptosis in human colorectal cancer HT-29 cells. VCP inhibition clearly changes the ubiquitination profile of RIPK1 and RIPK3 in the necrosome. RIPK1 interacts with VCP upon TNFÉ‘ stimulation in a complex separate from the necrosome or TNF Receptor 1 signaling complex.; Thesis (M.S.)--Tufts University, 2018.; Submitted to the Dept. of Pharmacology and Drug Development.; Advisor: Alexei Degterev.; Keyword: Pharmacology. %[ 2022-10-12 %9 Text %~ Tufts Digital Library %W Institution