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NF-kB p105

NF-kB p105. Introduction. NF-kB - transcription factors P105 P50 IkB Five types P105 – inactive P50 – active. NF-kB pathway. Orientation of p105. The N-terminal - p50. The C-terminal - IkB γ ,. Post-translational Processing Pathway. Moorthy AK. EMBO. 2006; 25(9): 1945-1956.

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NF-kB p105

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  1. NF-kB p105

  2. Introduction • NF-kB - transcription factors • P105 • P50 • IkB • Five types • P105 – inactive • P50 – active

  3. NF-kB pathway

  4. Orientation of p105 • The N-terminal - p50. • The C-terminal - IkBγ,

  5. Post-translational Processing Pathway Moorthy AK. EMBO. 2006; 25(9): 1945-1956.

  6. Structure of transcription factor • Dimer • RHR-c - dimerization • Sequence specific interactions

  7. IkBα • three main regions • Function

  8. IkB Cell. 1998; 95: 749-58.

  9. NLS of p65 interacting with IkB Cell. 1998; 95: 749-58.

  10. Cell. 1998; 95: 749-58.

  11. p50/p65 heterodimer • β-sheet sandwich • hydrophobic core • p50/p65 heterodimer greater stability than p50 homodimer • High DNA affinity

  12. P50/p65 heterodimer with IkB Cell. 1998; 95: 749-58.

  13. P50/p65 heterodimer bound to DNA Nature. 1998; 391: 410-3.

  14. Nature. 1998; 391: 410-3.

  15. Nature. 1998; 391: 410-3.

  16. Nature. 1998; 391: 410-3.

  17. p50/p65 DNA binding sites • Structure. 2002; 10(3): 383-391.

  18. Hodgkins Lymphoma • malignant tumors in the lymph system • Hodgkin and Reed-Sternberg (HRS) cells • Cells exhibit constitutive NF-kB activity • Cells resist apoptosis • Somatic hypermutation of Ig region • low affinity - die by Fas-mediated apoptosis • high affinity - stimulated to proliferate

  19. Treatment • IkB super repressor • bortezomib - Proteasome repressor • Novel solution – c-FLIP inhibitor

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