The nuclear receptor corepressor SMRT inhibits interstitial collagenase (MMP-1) transcription through an HRE-independent mechanism.
Nuclear receptors inhibit synthesis of collagenase-1 (matrix metalloproteinase-1; MMP-1), an enzyme that degrades interstitial collagens and contributes to joint pathology in rheumatoid arthritis. SMRT (Silencing Mediator for Retinoid and Thyroid hormone receptors) mediates the repressive effect of nuclear receptors at hormone responsive elements (HREs), prompting us to investigate whether this co-repressor could also regulate transcription of MMP-1, which lacks any known HREs. We find that primary synovial fibroblasts express SMRT. When over-expressed by transient transfection, SMRT inhibits MMP-1 promoter activity induced by interleukin-1 (IL-1), phorbol phorbol myristate acetate (PMA) or v-Src. SMRT apparently inhibits MMP-1 gene expression by interfering with one or more transcriptional elements clustered in a region between -321 and +63. We conclude that SMRT negatively regulates MMP-1 synthesis through a novel, HRE-independent mechanism that involves proximal regions of the MMP-1 promoter.
Schroen
D J
DJ
Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Chen
J D
JD
Vincenti
M P
MP
Brinckerhoff
C E
CE
D000818:Animals; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D017930:Genes, Reporter; D007375:Interleukin-1 / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1; D056985:Nuclear Receptor Co-Repressor 2; D015688:Oncogene Protein pp60(v-src) / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D011988:Receptors, Thyroid Hormone / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis / Q000502:physiology*; D013583:Synovial Membrane / Q000166:cytology / Q000201:enzymology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D056985:Nuclear Receptor Co-Repressor 2; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015688:Oncogene Protein pp60(v-src); D017364:Collagenases; D020781:Matrix Metalloproteinase 1; D013755:Tetradecanoylphorbol Acetate