A striking similarity in the organization of the E-selectin and beta interferon gene promoters.
Transcription of the endothelial leukocyte adhesion molecule 1 (E-selectin or ELAM-1) gene is induced by the inflammatory cytokines interleukin-1 beta and tumor necrosis factor alpha (TNF-alpha). In this report, we identify four positive regulatory domains (PDI to PDIV) in the E-selectin promoter that are required for maximal levels of TNF-alpha induction in endothelial cells. In vitro DNA binding studies reveal that two of the domains contain novel adjacent binding sites for the transcription factor NF-kappa B (PDIII and PDIV), a third corresponds to a recently described CRE/ATF site (PDII), and a fourth is a consensus NF-kappa B site (PDI). Mutations that decrease the binding of NF-kappa B to any one of the NF-kappa B binding sites in vitro abolished cytokine-induced E-selectin gene expression in vivo. Previous studies demonstrated a similar correlation between ATF binding to PDII and E-selectin gene expression. Here we show that the high-mobility-group protein I(Y) [HMG I(Y)] also binds specifically to the E-selectin promoter and thereby enhances the binding of both ATF-2 and NF-kappa B to the E-selectin promoter in vitro. Moreover, mutations that interfere with HMG I(Y) binding decrease the level of cytokine-induced E-selectin expression. The organization of the TNF-alpha-inducible element of the E-selectin promoter is remarkably similar to that of the virus-inducible promoter of the human beta interferon gene in that both promoters require NF-kappa B, ATF-2, and HMG I(Y). We propose that HMG I(Y) functions as a key architectural component in the assembly of inducible transcription activation complexes on both promoters.
Whitley
M Z
MZ
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Thanos
D
D
Read
M A
MA
Maniatis
T
T
Collins
T
T
D051698:Activating Transcription Factor 2; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects*; D013006:Growth Hormone / Q000096:biosynthesis / Q000235:genetics; D025741:HMGA1a Protein; D006609:High Mobility Group Proteins / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D020572:Oncogene Proteins v-rel; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D015815:Cell Adhesion Molecules; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D019040:E-Selectin; D006609:High Mobility Group Proteins; D016328:NF-kappa B; D020572:Oncogene Proteins v-rel; D011993:Recombinant Fusion Proteins; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; D025741:HMGA1a Protein; D016899:Interferon-beta; D013006:Growth Hormone