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Regulation of tissue inhibitor of metalloproteinase 1 gene transcription by RUNX1 and RUNX2

Regulation of tissue inhibitor of metalloproteinase 1 gene transcription by RUNX1 and RUNX2
Regulation of tissue inhibitor of metalloproteinase 1 gene transcription by RUNX1 and RUNX2
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.
24530-24539
Bertrand-Philippe, Marie
eb682e1e-b06e-472d-9a6c-7ad571a8834e
Ruddell, Richard G.
d506a0eb-6d09-44f9-8f51-25be5374b702
Arthur, Michael J.P.
d61d056b-6470-4afc-bafb-7a20be9cc413
Thomas, James
30f475d6-a285-4d94-8d38-942932237dff
Mungalsingh, Narenda
5a00c479-97a4-44b7-b7f8-766c32a791c9
Mann, Derek A.
7a0eb3d7-c2ca-432f-82a0-f4b0df08755d
Bertrand-Philippe, Marie
eb682e1e-b06e-472d-9a6c-7ad571a8834e
Ruddell, Richard G.
d506a0eb-6d09-44f9-8f51-25be5374b702
Arthur, Michael J.P.
d61d056b-6470-4afc-bafb-7a20be9cc413
Thomas, James
30f475d6-a285-4d94-8d38-942932237dff
Mungalsingh, Narenda
5a00c479-97a4-44b7-b7f8-766c32a791c9
Mann, Derek A.
7a0eb3d7-c2ca-432f-82a0-f4b0df08755d

Bertrand-Philippe, Marie, Ruddell, Richard G., Arthur, Michael J.P., Thomas, James, Mungalsingh, Narenda and Mann, Derek A. (2004) Regulation of tissue inhibitor of metalloproteinase 1 gene transcription by RUNX1 and RUNX2. The Journal of Biological Chemistry, 279 (23), 24530-24539. (doi:10.1074/jbc.M311804200).

Record type: Article

Abstract

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.

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Published date: 2004

Identifiers

Local EPrints ID: 26942
URI: https://eprints.soton.ac.uk/id/eprint/26942
PURE UUID: 6989b43c-9404-4155-bede-2fa71aeb8b55

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Date deposited: 25 Apr 2006
Last modified: 15 Jul 2019 19:13

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Contributors

Author: Marie Bertrand-Philippe
Author: Richard G. Ruddell
Author: Michael J.P. Arthur
Author: James Thomas
Author: Narenda Mungalsingh
Author: Derek A. Mann

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