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 phosphorylation of both c-Jun and ATF2. Transient overexpression of N-terminal truncated c-Jun or catalytically inactive Jun N-terminal kinase (JNK) 1 and 2 inhibits TNF-induced transcription of an E-selectin but not a kappa B promoter-reporter gene. Transient overexpression of the TRAF2 adaptor protein can activate NF-kappaB and endogenous JNK, whereas N-terminal truncated TRAF2 protein blocks TNF-induced NF-kappa B and JNK activation as well as E-selectin promoter-reporter gene transcription. Transient overexpression of RAC1 or CDC42, but not RAS, constitutively activates JNK and augments TNF-induced E-selectin transcription. Finally, 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 parallel TRAF-NF-kappa B and TRAF-RAC/CDC42-JNK-c-Jun/ATF2 pathways to initiate E-selectin transcription.
Min
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Molecular Cardiobiology Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
Pober
J S
JS
D051698:Activating Transcription Factor 2; D000954:Antigens, Surface / Q000096:biosynthesis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism / Q000502:physiology; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000276:immunology; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins; D020744:rac GTP-Binding Proteins
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D000954:Antigens, Surface; D017362:Cyclic AMP Response Element-Binding Protein; D019040:E-Selectin; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D018124:Receptors, Tumor Necrosis Factor; D014157:Transcription Factors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins