TNF INITIATES E-SELECTIN TRANSCRIPTION IN HUMAN ENDOTHELIAL-CELLS THROUGH PARALLEL TRAF-NF-KAPPA-B AND TRAF-RAC CDC42-JNK-C-JUN/ATF2 PATHWAYS/

TNF acts on the E-selectin gene promoter at three kappa B elements and at a variant cAMP-responsive element that binds ATF2/c-Jun. In human endothelial cells, TNF rapidly induces N-terminal domain phosphorylati on of both c-Jun and ATF2. Transient overexpression of N-terminal trun cated c-Jun or catalytically inactive Jun N-terminal kinase (JNK) 1 an d 2 inhibits TNF-induced transcription of an E-selectin but not a kapp a B promoter-reporter gene, Transient overexpression of the TRAF2 adap tor protein can activate NF-kappa B and endogenous JNK, whereas N-term inal truncated TRAF2 protein blocks TNF-induced NF-kappa B and JNK act ivation as well as E-selectin promoter-reporter gene transcription, Tr ansient overexpression of RAC1 or CDC42, but not RAS, constitutively a ctivates JNK and augments TNF-induced E-selectin transcription, Finall y, transient overexpression of catalytically inactive JNK or truncated TRAF2 partially inhibits endogenous E-selectin protein expression in human endothelial cells, These data suggest that TNF activates paralle l TRAF-NF-kappa B and TRAF-RAC/CDC42-JNK-c-Jun/ATF2 pathways to initia te E-selectin transcription.