Interleukin-1 or phorbol induction of the stromelysin promoter requires an element that cooperates with AP-1.
Interleukin-1, a mediator of inflammation, or tumor promoting phorbol esters induce transcription of stromelysin, a metalloproteinase that degrades extracellular matrix molecules and that is overexpressed in diseases such as rheumatoid arthritis. Sequences required for induction of transcription of the human stromelysin promoter are contained on a 46 base pair fragment. This fragment contains a sequence with a high degree of similarity to the binding site for the transcription factor activator protein-1 (AP-1) and indeed, the AP-1 sequence of this fragment is necessary but not sufficient for the maximal response to phorbol 12-myristate 13-acetate (phorbol) or interleukin-1. Maximal induction requires functional cooperation between the AP-1 sequence and a neighboring upstream regulatory sequence (URS) of the stromelysin promoter which is also necessary but not sufficient. We demonstrate that both the AP-1 sequence and the URS bind phorbol or interleukin-1 induced nuclear proteins. Cooperation of the AP-1 sequence with another sequence present in the stromelysin promoter may be a general mechanism whereby the AP-1 element, which is found in many promoters, achieves a maximal and specific response to various stimuli.
Sirum-Connolly
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Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03756.
Brinckerhoff
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D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000235:genetics*; D008969:Molecular Sequence Data; D010957:Plasmids; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun; D012045:Regulatory Sequences, Nucleic Acid; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D014157:Transcription Factors; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D013755:Tetradecanoylphorbol Acetate