Tumor Necrosis Factor-alpha(TNF-a Receptors and the NF-KB Path Diagram removed due to copyright considerations SeeTnf-a/nf-kbpathwaydiagramathttp://www.panomics.com/sr1000nfkb.ht TNF-a is made by macrophages and other cells of the immune system. Trimers of 3 identical cell-surface transmembrane proteins . TNF-a(hence the name) Lymphotoxin (LT; also known as TNF-p Mechanisms NF-kB resides in the cytosol bound to an inhibitor called IKB Binding of ligand to the receptor triggers phosphorylation of IKB IKB then becomes ubiquitinated and destroyed by proteasomes This liberates NF-kB so that it is now free to move into the nucleus where it acts as a transcription factor binding to the promoters and/or enhancers of more than 60 genes nF-kB got its name from its discovery as a transcription factor bound to the enhancer of the kappa light chain antibody gene encoding IL-1 and other cyt The monoclonal antibody Infliximab binds to TNF-a, and shows promise against some inf lammatory diseases such as rheumatoid arthritis urns on genes needed for cell proliferation, cell adhesion, and angiogenesis the US FDA approved a proteasome inhibitor, called bortezomib(Velcade@) of multiple myeloma, a cancer of plasma cells(we will learn more about it in theTumor Necrosis Factor-alpha (TNF-α) Receptors and the NF-κB Pathway Diagram removed due to copyright considerations. See TNF-a/NF-kB pathway diagram at http://www.panomics.com/sr1000nfkb.html. TNF-α is made by macrophages and other cells of the immune system. Receptors Trimers of 3 identical cell-surface transmembrane proteins. Ligands •TNF-α (hence the name) •Lymphotoxin (LT; also known as TNF-β) Mechanisms •NF-κB resides in the cytosol bound to an inhibitor called IκB. •Binding of ligand to the receptor triggers phosphorylation of IκB •IκB then becomes ubiquitinated and destroyed by proteasomes. •This liberates NF-κB so that it is now free to move into the nucleus where •it acts as a transcription factor binding to the promoters and/or enhancers of more than 60 genes: •NF-κB got its name from its discovery as a transcription factor bound to the enhancer of the kappa light chain antibody gene. •However, it also turns on the genes encoding IL-1 and other cytokines that promote inflammation. The monoclonal antibody Infliximab binds to TNF-α, and shows promise against some inflammatory diseases such as rheumatoid arthritis. •NF-κB also turns on genes needed for cell proliferation, cell adhesion, and angiogenesis. In May 2003, the US FDA approved a proteasome inhibitor, called bortezomib (Velcade®) for treatment of multiple myeloma, a cancer of plasma cells (we will learn more about it in the Session 13