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J. Biol. Chem., Vol. 279, Issue 23, 24530-24539, June 4, 2004

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Regulation of Tissue Inhibitor of Metalloproteinase 1 Gene Transcription by RUNX1 and RUNX2^*

Marie Bertrand-Philippe, Richard G. Ruddell, Michael J. P. Arthur, James Thomas, Narendra Mungalsingh, and Derek A. Mann

From the Liver Group, Division of Infection, Inflammation, and Repair, University of Southampton Medical School, Southampton General Hospital, Southampton SO16 6YD, United Kingdom

Tissue inhibitor of metalloproteinase 1 (TIMP1) is a contributory factor to fibrosis of a variety of organs including the liver. UTE-1 is a regulatory DNA motif essential for TIMP1 promoter activity in a variety of cell types including hepatic stellate cells (HSC), the key profibrogenic cells of the liver. In this study we identify RUNX1 and RUNX2 as UTE-1-binding proteins that are induced at the post-transcriptional level during activation of HSC. RUNX1 is expressed in at least two major isoforms, RUNX1B and RUNX1A. Overexpression of full-length RUNX1B isoform in HSC repressed TIMP1 promoter activity, whereas the truncated RUNX1A isoform and RUNX2 functioned as stimulators. To gain further understanding of the way in which RUNX1 isoforms differentially regulate TIMP1 transcription, we investigated the relationship between the UTE-1 site and its adjacent upstream serum-response element (SRE) in the promoter. The UTE-1 and SRE sites cooperate in a synergistic fashion to stimulate transcription of a heterologous minimal active promoter providing that they are in close proximity. The key regulatory sequence within the SRE is an AP-1 site that in HSC directs high level transcription via its interaction with JunD. RUNX1A was shown to interact directly with JunD, and by contrast RUNX1B failed to interact with JunD. Co-expression studies showed that RUNX1B can repress JunD-stimulated TIMP1 promoter activity. From these observations we propose that JunD and RUNX factors assemble at the adjacent SRE and UTE-1 sites in the TIMP1 promoter and form functional interactions that stimulate transcription. However, RUNX1B is unable to interact with JunD, and as such its occupancy at the UTE-1 site disrupts the optimal assembly of transcriptional activators required for directing high level TIMP1 promoter function.

Received for publication, October 28, 2003 , and in revised form, March 23, 2004.

^* This work was supported in part by UK Medical Research Grants G9900951 and G9900297 (to D. A. M. and M. J. P. A.) and Wellcome Trust Grants 068524/Z/02/Z and 069084/Z/02/Z (to D. A. M. and M. J. P. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of British Liver Trust Ph.D. studentship.

To whom correspondence should be addressed: Liver Group, Division of Infection, Inflammation, and Repair, Level D, South Academic Block, Southampton General Hospital, Southampton SO16 6YD, UK. Tel.: 442380796871; Fax: 442380798519; E-mail: dam2{at}soton.ac.uk.

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