A human-specific TNF-responsive promoter for Goodpasture antigen-binding protein.
The Goodpasture antigen-binding protein, GPBP, is a serine/threonine kinase whose relative expression increases in autoimmune processes. Tumor necrosis factor (TNF) is a pro-inflammatory cytokine implicated in autoimmune pathogenesis. Here we show that COL4A3BP, the gene encoding GPBP, maps head-to-head with POLK, the gene encoding for DNA polymerase kappa (pol kappa), and shares with it a 140-bp promoter containing a Sp1 site, a TATA-like element, and a nuclear factor kappa B (NFkappaB)-like site. These three elements cooperate in the assembly of a bidirectional transcription complex containing abundant Sp1 and little NFkappaB that is more efficient in the POLK direction. Tumour necrosis factor cell induction is associated with Sp1 release, NFkappaB recruitment and assembly of a complex comparatively more efficient in the COL4A3BP direction. This is accomplished by competitive binding of Sp1 and NFkappaB to a DNA element encompassing a NFkappaB-like site that is pivotal for the 140-bp promoter to function. Consistently, a murine homologous DNA region, which contains the Sp1 site and the TATA-like element but is devoid of the NFkappaB-like site, does not show transcriptional activity in transient gene expression assays. Our findings identify a human-specific TNF-responsive transcriptional unit that locates GPBP in the signalling cascade of TNF and substantiates previous observations, which independently related TNF and GPBP with human autoimmunity.
Granero
Froilán
F
Centro de Investigación Príncipe Felipe, Valencia, Spain.
Revert
Fernando
F
Revert-Ros
Francisco
F
Lainez
Sergio
S
Martínez-Martínez
Pilar
P
Saus
Juan
J
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D021901:DNA, Intergenic / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016372:RNA, Antisense / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016385:TATA Box / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000494:pharmacology*; D000099270:Y-Family DNA Polymerases
D021901:DNA, Intergenic; D004259:DNA-Directed DNA Polymerase; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D016372:RNA, Antisense; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; C119090:CERT1 protein, human; C404302:POLK protein, human; D000099270:Y-Family DNA Polymerases