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Unique Inhibition of IKK Activity by Aspirin and Salicylate in NF-kB Regulation

This study investigates the effects of aspirin (ASA) and salicylate on IKK activity and NF-kB regulation in human cells. Unlike other anti-inflammatory agents, ASA and salicylate uniquely inhibit IKK activity without affecting prostaglandin synthesis. Inhibition is primarily associated with IKKbeta, and this effect is observed both in vitro and in vivo. Additionally, the role of the deubiquitinating enzyme CYLD in NF-kB activation and its implications for cancer are explored, revealing potential mechanisms for increased cell proliferation upon CYLD knockdown.

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Unique Inhibition of IKK Activity by Aspirin and Salicylate in NF-kB Regulation

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  1. 1994 “IkB concentrations in the salicylate cell extracts were the same as in control whereas IkB was reduced in activated cells without salicylate” 20mM aspirin

  2. NFkB NFkB CREB Not seeing the same inhibition profile as other antiinflammatory agents.

  3. Other antiinflammatory drugs inhibit prostaglandin synthesis but they do not alter IKK activity

  4. Inhibition of IKK activity is unique to ASA and Sal Only IKKbeta inhibited

  5. Other pathways Effective [ASA] 1-5mM

  6. IKK SS->EE mutations (constitutively active) Not upstream of IKK

  7. Recombinant IKK beta - same trend as “in vivo”

  8. “in vivo” “in vitro” 80uM 30-50uM

  9. Suggest not covalently bound

  10. “preincubation” Inhibition of kinase activity [] dept. of aspirin

  11. How does this relate to cancer?

  12. Many Faces of Ubiquitin - Deubiquitinating Enzymes

  13. Familial Cylindromatosis (benign tumors) Usually on forehead and scalp Dominantly inherited due to loss of the tumor suppressor: CYLD

  14. Used siRNA to knockdown expression of CYLD PMA (phorbol ester) stimulates NFkB via IkBalpha degradation When “KD” CYLD - increased proliferation

  15. 16hours later

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