ATF3 represses 72-kDa type IV collagenase (MMP-2) expression by antagonizing p53-dependent trans-activation of the collagenase promoter

Chunhong Yan, Heng Wang, Douglas D. Boyd

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

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 γ-irradiation-induced slowed G2/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.

Original languageEnglish (US)
Pages (from-to)10804-10812
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number13
DOIs
StatePublished - Mar 29 2002
Externally publishedYes

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Matrix Metalloproteinase 8
Matrix Metalloproteinase 2
Collagenases
Matrix Metalloproteinases
Chemical activation
Cell Cycle
Activating Transcription Factor 3
Cells
p53 Genes
Transcription Factor AP-1
Response Elements
Transcription
Luciferases
Base Pairing
Transcriptional Activation
Tumors
Assays
Proteins
Clone Cells
Genes

ASJC Scopus subject areas

  • Biochemistry

Cite this

ATF3 represses 72-kDa type IV collagenase (MMP-2) expression by antagonizing p53-dependent trans-activation of the collagenase promoter. / Yan, Chunhong; Wang, Heng; Boyd, Douglas D.

In: Journal of Biological Chemistry, Vol. 277, No. 13, 29.03.2002, p. 10804-10812.

Research output: Contribution to journalArticle

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