p53 down-regulates matrix metalloproteinase-1 by targeting the communications between AP-1 and the basal transcription complex

We have previously reported that human matrix metalloproteinase‐1 (MMP1) is a p53 target gene subject to down‐regulation (Sun et al. [1999]: J Biol Chem 274:11535–11540]. In the present study, we demonstrate that the down‐regulation of the human −83MMP1 promoter fragment by p53 was abolished when the −72AP‐1 site was eliminated and that a GAL4‐cJun‐mediated but not a GAL4‐Elk1‐mediated induction of pFR‐luci was effectively inhibited by p53 suggesting an AP‐1 dependent but AP‐1 binding independent mechanism. Results from gel mobility shift assays were consistent with an AP‐1 binding independent mechanism. We also demonstrate that both p300 and TATA box binding proteins cooperated with the transcription factor AP‐1 to induce the promoter of MMP1; however, p53 only inhibited the p300‐mediated induction of the MMP1 promoter and the inhibition was −72AP‐1 dependent. Furthermore, the down‐regulation of the MMP1 promoter and mRNA by p53 could be reversed by p300 and by a p53 binding p300 fragment that had no coactivator activity. Taken together, these results indicate that p53 down‐regulates MMP1 mainly by disrupting the communications between the transactivator AP‐1 and the basal transcriptional complex, which are partially mediated by p300. Finally, by using p53 truncated mutant constructs, we demonstrate that both the N‐terminal activation domain and the C‐terminal oligomerization domains of p53 were required for the down‐regulation of MMP1 transcription. © 2004 Wiley‐Liss, Inc.