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Stromelysin-1 expression is activated in vivo by Ets-1 through palindromic head-to-head Ets binding sites present in the promoter

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Abstract

Regulation of the gene expression of Stromelysin-1 (matrix metalloproteinase-3), a member of the matrix metalloproteinase family, is critical for tissue homeostasis. The Stromelysin-1 promoter is known to be transactivated by Ets proteins through palindromic head-to-head Ets binding sites (EBS), an unusual configuration among metalloproteinase promoters. Patterns of increased co-expression of Stromelysin-1 and Ets-1 genes have been observed in pathological processes such as rheumatoid arthritis, glomerulonephritis and tumor invasion. In this context, we show in a synovial fibroblastic model cell line (HIG-82), which is able to co-express Stromelysin-1 and Ets-1, that the EBS palindrome is essential for the expression of Stromelysin-1. More precisely, using electrophoretic mobility shift assays, DNA affinity purification and chromatin immunoprecipitation, we demonstrate that endogenous Ets-1, but not Ets-2, is present on this palindrome. The use of a dominant-negative form of Ets-1 and the decrease of Ets-1 amount either by fumagillin, an antiangiogenic compound, or by short interfering RNA show that the activation rate of the promoter and the expression of Stromelysin-1 correlate with the level of endogenous Ets-1. Thus, it is the first demonstration, using this cellular model, that endogenously expressed Ets-1 is actually a main activator of the Stromelysin-1 promoter through its effective binding to the EBS palindrome.

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Acknowledgements

We thank Drs J Coll and Y Rouillé for generous gift of pSUPER constructs, Dr D Tulasne for practical guidance and C Lagrou for technical assistance. We are grateful to Dr V Fafeur and Dr V Mattot for providing pCDNA3-Ets-1dn construct. This work was supported by a grant from the Comité du Nord de la Ligue contre le Cancer. The Ligue Nationale contre le Cancer provided student fellowships for David Baillat and Gabriel Leprivier and a postdoctoral fellowship for Dr Nadejda Vintonenko.

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  1. D Baillat

    Present address: The Wistar Institute, 3601 Spruce street, Philadelphia, PA, 19104, USA

  2. D Régnier

    Present address: INSERM U 407, Faculté de Médecine de Lyon-Sud, B.P. 12, 69921, Oullins Cedex, France

  3. D Baillat and G Leprivier: These authors contributed equally to this work.

Authors and Affiliations

  1. CNRS Unité Mixte de Recherche 8526, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille II, Lille Cedex, France

    D Baillat, G Leprivier, D Régnier, N Vintonenko, A Bègue, D Stéhelin & M Aumercier

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  1. D Baillat
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Correspondence to M Aumercier.

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Baillat, D., Leprivier, G., Régnier, D. et al. Stromelysin-1 expression is activated in vivo by Ets-1 through palindromic head-to-head Ets binding sites present in the promoter. Oncogene 25, 5764–5776 (2006). https://doi.org/10.1038/sj.onc.1209583

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