A novel enhancer element in the human IL-4 promoter is suppressed by a position-independent silencer.
IL-4 is a pleiotropic cytokine that regulates T cell-dependent immune responses. We identified and characterized a novel enhancer, positive regulatory element I (PRE-I), in the 5' region of the promoter of the human IL-4 gene. The functional core element of PRE-I is -239GTGTAATTTCCTATGC-224. Two novel nuclear proteins, POS-1 and POS-2, were found to specifically bind to the core element and function as transcriptional activators. The function of PRE-I did not require T cell stimulation and was not restricted to T cells. However, mutations in the core element of PRE-I significantly reduced the promoter activity and completely impaired inducibility of the promoter. In the human IL-4 promoter the enhancer function of PRE-I is strongly suppressed. A negative regulatory element (NRE), 45 bp upstream of PRE-I, directly represses PRE-I enhancer activity. Repression of PRE-I by NRE does not require a particular order or arrangement of positive and negative regulatory sequences. The IL-4 NRE may also down-regulate other enhancers, such as the murine sarcoma virus and the SV40 enhancers. Thus, the IL-4 NRE may represent a new type of cis regulatory element that carries the properties of a silencer but down-regulates enhancer instead of basal promoter activity.
Tumor Immunology Program, German Cancer Research Center Heidelberg.
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Li-Weber
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Krafft
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Krammer
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000235:genetics*; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D009053:Sarcoma Viruses, Murine / Q000235:genetics; D013539:Simian virus 40 / Q000235:genetics; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D015847:Interleukin-4