A molecular mechanism for the differential regulation of TGF-beta1 expression due to the common SNP -509C-T (c. -1347C > T).
Transforming growth factor beta1 (TGF-beta1) levels influence many cellular, immunologic and pathologic processes. Activator protein 1 (AP1) and hypoxia are key regulators of TGF-beta1 expression levels. The common TGFB1 promoter SNP c.-1347C > T (-509C-T, rs1800469) has been linked to a nearly twofold difference in plasma levels among individuals and with risk, progression, and outcome of numerous diseases. We demonstrate exclusive in vitro and in vivo recruitment of AP1 containing JunD to -1347C. This study also is the first to demonstrate hypoxia inducible factor 1 (HIF-1) binding to the TGFB1 promoter. HIF-1 was found to associate with both -1347C and -1347T and compete with AP1 for binding to -1347C. Reporter constructs demonstrate that expression differences between -1347C and -1347T are due to selective AP1 recruitment to the TGFB1 promoter. As AP1 is known to down-regulate transcription of other genes, we suggest that the molecular mechanism for the difference in TGF-beta1 plasma levels linked to -1347 is due to transcriptional suppression by AP1 binding to -1347C. These data should aid in our understanding of the association of the -1347 SNP with the pathogenesis of certain TGF-beta1-related diseases.
Shah
Riddhish
R
Department of Oncology, Georgetown University Medical Center, Washington, DC 20007, USA.
Hurley
Carolyn K
CK
Posch
Phillip E
PE
D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D015345:Oligonucleotide Probes / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
D051793:Hypoxia-Inducible Factor 1; D015345:Oligonucleotide Probes; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D008156:Luciferases