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.
Sun
Yubo
Y
Department of Medicine, University of Miami School of Medicine, Miami, Florida 33101, USA. ysun@med.miami.edu
Zeng
Xiao-Rong
XR
Wenger
Leonor
L
Firestein
Gary S
GS
Cheung
Herman S
HS
D001665:Binding Sites; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D020781:Matrix Metalloproteinase 1