Transcriptional induction of stromelysin-3 in mesodermal cells is mediated by an upstream CCAAT/enhancer-binding protein element associated with a DNase I-hypersensitive site.
Stromelysin-3 (ST3) is a matrix metalloproteinase whose synthesis is markedly increased in stromal fibroblasts of most invasive human carcinomas. In the present study, we have investigated the molecular mechanisms by which high levels of ST3 expression can be induced. In contrast to the early and transient induction of interstitial collagenase by 12-O-tetradecanoylphorbol-13-acetate (TPA), the fibroblastic induction of ST3 was found to be delayed and to require protein neosynthesis. We demonstrated that this induction is transcriptional and does not result from changes in RNA stability. By looking next to promoter regions accessible to DNase I upon gene induction, we have identified two distal elements and have characterized their role in the transcriptional regulation of ST3. The first one is a TPA-responsive element that controls the base-line ST3 promoter activity but is not required for its activation. We demonstrate that ST3 gene induction is actually mediated by the second element, a C/EBP-binding site, by showing: (i) that this element becomes accessible in cells induced to express ST3, (ii) that endogenous C/EBPbeta binds to the ST3 promoter, and (iii) that this binding leads to ST3 transcriptional activation. Our study provides new insights into the regulation of ST3 and suggests an additional role for C/EBP transcription factors in tissue remodeling processes associated with this MMP.
Luo
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Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM, Université Louis Pasteur, Communauté Urbaine de Strasbourg, 67404 Illkirch cedex, France.
Guérin
E
E
Ludwig
M G
MG
Stoll
I
I
Basset
P
P
Anglard
P
P
D022762:CCAAT-Enhancer-Binding Proteins; D002478:Cells, Cultured; D017364:Collagenases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D003850:Deoxyribonuclease I / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053507:Matrix Metalloproteinase 11; D020782:Matrix Metalloproteinases / Q000235:genetics*; D008666:Metalloendopeptidases; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D003850:Deoxyribonuclease I; D017364:Collagenases; D053507:Matrix Metalloproteinase 11; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D013755:Tetradecanoylphorbol Acetate