title: PU.1 is required for transcriptional activation of the Stat6 response element in the Igepsilon promoter.
abstract: Signal transducer and activator of transcription 6 (Stat6) has a crucial role in regulation of IL-4-induced gene responses. Stat6-binding sites are present in the promoters of both ubiquitously and cell-type-specifically expressed genes. The promoter regions of IL-4-inducible genes contain cis-acting elements for several transcription factors that act in concert with Stat6 and are also likely to modulate lineage-specific gene expression. We have observed that the Stat6 response element from the B-cell-specific Igepsilon promoter is readily activated upon IL-4 stimulation in B cells but not in non-hematopoietic cells. A minimal low-affinity PU.1-core-binding sequence (5'-AGAA-3') was identified within the Stat6 DNA-binding site in the Igepsilon promoter. Ectopic expression of the myeloid- and B-cell-specific transcription factor PU.1 restored the IL-4-inducibility of the Igepsilon-Stat6 response element in HepG2 cells, and the induction required an intact PU.1-binding sequence. Both the transactivation and the DNA-binding domains of PU.1 were required for induction of Stat6-mediated transcription. The co-operation between PU.1 and Stat6 in transactivation of the Igepsilon gene represents a molecular mechanism for the fine-tuning of cell-type-restricted expression of IL-4-induced gene responses.
authors.affiliation: Institute of Medical Technology, University of Tampere, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Pesu
authors.forename: Saara
authors.initials: S
authors.lastname: Aittomäki
authors.forename: Tuuli
authors.initials: T
authors.lastname: Välineva
authors.forename: Olli
authors.initials: O
authors.lastname: Silvennoinen
mesh_terms: D001665:Binding Sites; D002051:Burkitt Lymphoma / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005803:Genes, Immunoglobulin; D017930:Genes, Reporter; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics*; D015847:Interleukin-4 / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000737:chemistry / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D007073:Immunoglobulin E; D015847:Interleukin-4; D011518:Proto-Oncogene Proteins; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494101:STAT6 protein, human