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

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.



1994

20mM aspirin“IkB concentrations in the salicylatecell extracts were the same as in controlwhereas IkB was reduced in activated cellswithout salicylate”




are needed to see this picture.QuickTime™ and a

TIFF (LZW) decompressorare needed to see this picture.

Not seeing the same inhibition profile as other antiinflammatory agents.

CREBNFkB NFkB




Other antiinflammatory drugs inhibit prostaglandin synthesisbut they do not alter IKK activity



Inhibition of IKK activity is unique to ASA and Sal

Only IKKbeta inhibited




Effective [ASA] 1-5mMOther pathways



IKK SS->EE mutations (constitutively active)

Not upstream of IKK



Recombinant IKK beta - same trend as “in vivo”



“in vivo” “in vitro”

80uM 30-50uM



Suggest not covalently bound



Inhibition of kinase activity [] dept. of aspirin

“preincubation”

How does this relate to cancer?





Many Faces of Ubiquitin - Deubiquitinating Enzymes



Familial Cylindromatosis(benign tumors)

Usually on forehead and scalp

Dominantly inheriteddue to loss of the tumor suppressor:

CYLD



Used siRNA to knockdown expression of CYLD

PMA (phorbol ester) stimulates NFkB via IkBalpha degradation

When “KD” CYLD - increased proliferation



16hours later



Documents

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