Transcriptional repression of the human collagenase-1 (MMP-1) gene in MDA231 breast cancer cells by all-trans-retinoic acid requires distal regions of the promoter.

Abstract

In the present study, we investigated the mechanisms controlling constitutive transcription of collagenase-1 and its repression by all-trans-retinoic acid (RA) in the highly invasive metastatic and oestrogen-receptor-negative breast cancer cell line MDA231. A combination of in vivo and in vitro experiments that include DNAase I hypersensitivity assays, transient transfection of collagenase-1 promoter constructs, and electrophoretic mobility shift assays implicate several PEA3 sites, binding sites for Ets-related transcription factors, in the constitutive expression of the human collagenase-1 promoter. Transient transfection of promoter constructs linked to the luciferase reporter, along with gel retardation assays, revealed that repression of collagenase-1 transcription by RA is not dependent on the proximal AP-1 site, but, rather, requires sequences located in distal regions of the promoter. Transcriptional analyses and electrophoretic mobility shift assays suggest that the PEA3 site located at -3108 bp facilitates, at least in part, the transcriptional repression of the human collagenase-1 gene in MDA231 cells. We conclude that collagenase-1 repression in MDA231 cells occurs by a novel regulatory pathway that does not depend on the proximal AP-1 site at -73 bp, but does depend on distal regions in the collagenase-1 promoter.

• Authors: U Benbow, J L Rutter, C H Lowrey, C E Brinckerhoff
• Journal: British journal of cancer (Br J Cancer) Vol. 79 Issue 2 Pg. 221-8 (Jan 1999) ISSN: 0007-0920 [Print] England
• PMID: 9888461 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Matrix Metalloproteinase Inhibitors
• Neoplasm Proteins
• RARA protein, human
• Receptors, Retinoic Acid
• Retinoic Acid Receptor alpha
• retinoic acid receptor beta
• retinoic acid receptor gamma
• Tretinoin
• Deoxyribonuclease I
• Collagenases
• Matrix Metalloproteinase 1

Topics

• Collagenases (biosynthesis, genetics)
• Deoxyribonuclease I (pharmacology)
• Enzyme Repression (genetics)
• Female
• Gene Expression (drug effects)
• Humans
• Matrix Metalloproteinase 1
• Matrix Metalloproteinase Inhibitors
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Promoter Regions, Genetic
• Receptors, Retinoic Acid (drug effects, metabolism)
• Retinoic Acid Receptor alpha
• Transcription, Genetic (drug effects)
• Transfection
• Tretinoin (pharmacology)
• Tumor Cells, Cultured (drug effects)