ATF3 represses 72-kDa type IV collagenase (MMP-2) expression by antagonizing p53-dependent trans-activation of the collagenase promoter.
The murine homologue of the ATF3 transcription factor increases tumor metastases but, surprisingly, represses 72-kDa type IV metalloproteinase (MMP-2) expression. The current study describes a novel mechanism by which ATF3 regulates transcription. Progressive deletions of the MMP-2 promoter indicated a 38-base pair region (-1659/-1622) necessary for the ATF3-mediated repression. This region lacked CREB/AP-1 motifs but contained a consensus p53 motif shown previously to regulate MMP-2 expression. The activity of a p53 response element-driven luciferase reporter was reduced in ATF3-expressing HT1080 clones. Although MMP-2 promoter activity was not repressed by ATF3 in p53-deficient Saos-2 cells, p53 re-expression increased MMP-2 promoter activity and restored the sensitivity to ATF3. The activity of a GAL4-driven reporter in HT1080 cells co-expressing the full-length p53 sequence fused to the GAL4 DNA binding domain was diminished by ATF3. p53-ATF3 protein-protein interactions were demonstrated both in vivo and in vitro. Cell cycle analysis, performed as an independent assay of p53 function, revealed that gamma-irradiation-induced slowed G(2)/M cell cycle progression (attributable to p53) was countered by ATF3. Thus, ATF3 represses MMP-2 expression by decreasing the trans-activation of this gene by p53.
Yan
Chunhong
C
Department of Cancer Biology, M. D. Anderson Cancer Center, Houston, Texas 77030.
Wang
Heng
H
Boyd
Douglas D
DD
D051700:Activating Transcription Factor 3; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D016195:G2 Phase / Q000528:radiation effects; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011839:Radiation, Ionizing; D012097:Repressor Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000502:physiology
D051700:Activating Transcription Factor 3; D017931:DNA Primers; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D020778:Matrix Metalloproteinase 2