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BC212 Signal transduction & growth control Death receptor signaling

BC212 Signal transduction & growth control Death receptor signaling. Lecture overview. Death receptor signaling pathways: TNF/TNFR gene-families DISC signaling NF-kappaB signaling ------------------------------------------ Discussion: FLIP: a switch between death & survival?.

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BC212 Signal transduction & growth control Death receptor signaling

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  1. BC212Signal transduction & growth controlDeath receptor signaling BC212/week7/2003

  2. Lecture overview • Death receptor signaling pathways: • TNF/TNFR gene-families • DISC signaling • NF-kappaB signaling • ------------------------------------------ • Discussion: FLIP: a switch between death & survival? BC212/week7/2003

  3. Lecture overview • Death receptor signaling pathways: • TNF/TNFR gene-families BC212/week7/2003

  4. TNF/TNFR families • Ligands = typically membrane bound; at least 18 • Receptors = one subunit; at least 28 • Receptor-ligand promiscuity • Decoy receptors • Trimerization • PLAD: pre-ligand assembly domain BC212/week7/2003

  5. TNF/TNFR families Ashkenazi Nat Rev Cancer 2:420, 2002 BC212/week7/2003

  6. TNF/TNFR families • Ligands = typically membrane bound; at least 18 • Receptors = one subunit; at least 28 • Receptor-ligand promiscuity • Decoy receptors • Trimerization • PLAD: pre-ligand assembly domain BC212/week7/2003

  7. TNF/TNFR families Ashkenazi Nat Rev Cancer 2:420, 2002 BC212/week7/2003

  8. TNF/TNFR families Goldstein Science 288:2388, 2000 BC212/week7/2003

  9. TNF/TNFR families PLAD: pre-ligand assembly domain ALS (autoimmune lymphoproliferative syndrome): del 52-96 (het) Siegel et al. Science 288:2354, 2000 BC212/week7/2003

  10. Lecture overview • Death receptor signaling pathways: • TNF/TNFR gene-families • DISC signaling BC212/week7/2003

  11. DISC signaling • Cell death, survival and cancer • Intrinsic versus extrinsic death pathways BC212/week7/2003

  12. DISC signaling Lost track of this reference BC212/week7/2003

  13. DISC signaling • Death receptor ligands • TRAIL (DR4, DR5) • FasL (Fas) • TNF (TNFR1) • TWEAK (TWEAK-R) BC212/week7/2003

  14. DISC signaling BC212/week7/2003

  15. DISC signaling • Death receptor pathway components: • FADD • DD & DED • Caspase-8, -10 • DED & caspase (protease) • FLIP • Dominant inhibitor caspase relative • Caspase-3 (etc.) • Extrinsic pathway (via Bid) BC212/week7/2003

  16. DISC signaling Ashkenazi Nat Rev Cancer 2:420, 2002 BC212/week7/2003

  17. DISC signaling BC212/week7/2003

  18. DISC signaling BC212/week7/2003

  19. DISC signaling • Identifying components • Fas • screen for cytotoxic antibodies • antibody crosslinks/multimerizes Fas • FasL • cell line which killed Fas-expressing cells (only) • FasFc blocked killing • Used biotinylated FasFc to affinity purify FasL • FADD • two-hybrid screen for DD interactors BC212/week7/2003

  20. DISC signaling • lpr and gld mice • Lymphoproliferative phenotype • Resembles SLE • lpr: homozygous mutation in Fas DD • gld: homozygous inactivating mutation in FasL • Implicates Fas-FasL in immune cell apoptosis BC212/week7/2003

  21. DISC signaling Ashkenazi Nat Rev Cancer 2:420, 2002 BC212/week7/2003

  22. DISC signaling • Induced proximity model of caspase activation • Parallels with kinase activation • Evidence: • i) artificial dimerization activates caspase • ii) zymogen has low, but detectable, activity BC212/week7/2003

  23. Lecture overview • Death receptor signaling pathways: • TNF/TNFR gene-families • DISC signaling • NF-kappaB signaling BC212/week7/2003

  24. NFkappaB signaling Haefner Drug Discovery Today 7:653 2002 BC212/week7/2003

  25. NFkappaB signaling Karin, et al Nat Rev Cancer 2:301, 2002 BC212/week7/2003

  26. NFkappaB signaling Haefner Drug Discovery Today 7:653 2002 BC212/week7/2003

  27. NFkappaB signaling Karin, et al Nat Rev Cancer 2:301, 2002 BC212/week7/2003

  28. NFkappaB signaling Karin, et al Nat Rev Cancer 2:301, 2002 BC212/week7/2003

  29. NFkappaB signaling • Evidence linking NFkappaB to proliferation/cancer • RelA: viral NFkappaB homolog • incrd stability; decrd susceptibility to degradation • Bcl3: chromosomal translocations in leukemia • over-expression • NFKB2: chromosomal translocation in leukemia/lymphoma • deletes IkappaB part BC212/week7/2003

  30. NFkappaB signaling • Evidence establishing mechanism of NFkappaB signaling • Isolation via enhancer affinity chromatography • PMA (cells) & DOC (extracts) induces EMSA activity • PMA stimulates transport to the nucleus • DOC-dissociable inhibitor (IkappaB) • NFkB-IkB complex disrupted, EMSA induced, by PKC • IkB degradation: proteosome inhs, Ub’n, etc. BC212/week7/2003

  31. NFkappaB signaling BC212/week7/2003

  32. NFkappaB signaling BC212/week7/2003

  33. Lecture overview • Death receptor signaling pathways: • TNF/TNFR gene-families • DISC signaling • NF-kappaB signaling • ------------------------------------------ • Discussion: FLIP: a switch between death & survival? BC212/week7/2003

  34. FLIP as a switch? BC212/week7/2003

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