P53 down-regulates matrix metalloproteinase-1 by targeting the communications between AP-1 and the basal transcription complex

J Cell Biochem. 2004 May 15;92(2):258-69. doi: 10.1002/jcb.20044.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Down-Regulation*
  • HeLa Cells
  • Humans
  • Matrix Metalloproteinase 1 / genetics*
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Mutation / genetics
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Proto-Oncogene Proteins c-jun / metabolism
  • Trans-Activators / metabolism
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic*
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Multiprotein Complexes
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-jun
  • Trans-Activators
  • Transcription Factor AP-1
  • Tumor Suppressor Protein p53
  • Matrix Metalloproteinase 1