Negative regulation of the rat stromelysin gene promoter by retinoic acid is mediated by an AP1 binding site.

Abstract

Stromelysin is a member of the metalloproteinase family which plays an important role in extracellular matrix remodelling during many normal and disease processes. We show here that in polyomavirus‐transformed rat embryo fibroblast cells (PyT21), the transcription from the stromelysin gene is repressed by the vitamin A derivative retinoic acid (RA). Furthermore, expression vectors encoding the human RA receptors hRAR‐alpha, hRAR‐beta and hRAR‐gamma repress chloramphenicol acetyltransferase (CAT) expression from stromelysin promoter‐CAT gene expression vectors in RA‐treated PyT21 and human HeLa cells, as determined by transient transfection assays. Through mutation and deletion analysis, we show that the RA dependent repression is mediated by a 25 bp region from nucleotide positions ‐72 to ‐48 of the rat stromelysin 5′‐flanking DNA sequence. Further mutation analysis of this region indicates that the DNA sequence required for RA dependent repression colocalizes with an AP1 binding site which is essential for promoter activity. We show also that RA represses the transcriptional activity of a reporter gene containing a TPA responding AP1 binding site driving the HSV tk promoter. Thus the RAR‐RA complex appears to repress transcription of the stromelysin gene by blocking activation by positive regulatory factors. However, we found no evidence supporting the possibility that the RA dependent repression could be due to RAR binding to the AP1 binding site or to the AP1 components c‐fos and c‐jun.

Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-β in liver stellate cells

“…44 Several previous A hepatotoxicity. 40 The suppression of stromelysin and colla-studies have shown that both RA and retinol may reduce genase gene promoters by RA 41,42 may partly account for this SC proliferation both in basal conditions, [45][46][47] and following fibrosis-enhancing effect. Previously, we have observed that stimulation with growth factors involved in liver inflammanthe acyclic retinoid used in the current study reduces the tion.…”

Retinoid-induced activation of NF-κB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells

“…In addition to inducing transcription, liganted receptors can also affect the activity of other transcription factors. In particular, retinoid receptors are known to repress growthstimulating transcription factor AP1 (Jun/Fos) (Nicholson et al, 1990). Of note, retinoids can also modulate the activity of the transcription factor NF-kB.…”

AP-1 transrepressing retinoic acid does not deplete coactivators or AP-1 monomers but may target specific Jun or Fos containing dimers

“…A crosslinking and coprecipitation approach suggested that RAR can physically associate with both c-Jun and cFos (Yang-Yen et al, 1991). However, these proteinprotein interactions appear to be weak or indirect, since our data and other reports suggest that direct interaction between AP-1 and RAR is unlikely (Nicholson et al, 1990). p300 and SRC-1 can act as coactivators for RAR or AP-1 mediated transcription (Kamei et al, 1996;Lee et al, 1998).…”