p53 down-regulates human matrix metalloproteinase-1 (collagenase-1) gene expression

Yubo Sun, Yi Sun, Leonor Wenger, Joni L. Rutter, Constance E. Brinckerhoff, Herman S Cheung

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Abstract

Recent studies show that the p53 tumor suppressor protein is overexpressed in rheumatoid arthritis (RA) synovium and that somatic mutations previously identified in human tumors are present in RA synovium (Firestein, G. S., Echeverri, F., Yeo, M., Zvaifler, N. J., and Green, D. R. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 10895-10900; Firestein, G. S., Nguyen, K., Aupperle, K. R., Yeo, M., Boyle, D. L., and Zvaifler, N. J. (1996) Am. J. Pathol. 149, 2143-2151; Reme, T., Travaglio, A., Gueydon, E., Adla, L., Jorgensen, C., and Sany, J. (1998) Clin. Exp. Immunol. 111, 353- 3581). We hypothesize that the abnormality of p53 seen in RA synovium may contribute to joint degeneration through the regulation of human matrix metalloproteinase-1 (hMMP-1, collagenase-1) gene expression. Transcription assays were performed with luciferase reporters driven by the promoter of the hMMP-1 gene or by a minimal promoter containing tandem repeats of the consensus binding sequence for activator protein-1, cotransfected with p53- expressing plasmids. The results revealed that (i) wild-type (wt) p53 down- regulated the promoter activity of hMMP-1 in a dose-dependent fashion; (ii) four of six p53 mutants (commonly found in human cancers) lost this repression activity; and (iii) this p53 repression activity was mediated at least in part by the activator protein-1 sites found in the hMMP-1 promoter. These findings were further confirmed by Northern analysis. The down- regulation of hMMP-1 gene expression by endogenous wt-p53 was shown by treatment of U2-OS cells, a wt-p53-containing osteogenic sarcoma line, and Saos-2 cells, a p53-negative osteogenic sarcoma line, with etoposide, a potent inducer of p53 expression. p53, activated by etoposide, appears to block hMMP-1 promoter activity induced by etoposide in U2-OS cells. In summary, we have shown for the first time that the hMMP-1 gene is a p53 target gene, subject to p53 repression. Because MMP-1 is principally responsible for the irreversible destruction of collagen in articular tissue in RA, abnormality of p53 may contribute to joint degeneration through the regulation of MMP-1 expression.

Original languageEnglish
Pages (from-to)11535-11540
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number17
DOIs
StatePublished - Apr 23 1999

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Etoposide
Gene expression
Synovial Membrane
Rheumatoid Arthritis
Down-Regulation
Genes
Transcription Factor AP-1
Matrix Metalloproteinases
Gene Expression
Joints
Osteosarcoma
Tumor Suppressor Protein p53
Tandem Repeat Sequences
Transcription
Luciferases
Tumors
Assays
p53 Genes
Consensus Sequence
Plasmids

ASJC Scopus subject areas

  • Biochemistry

Cite this

p53 down-regulates human matrix metalloproteinase-1 (collagenase-1) gene expression. / Sun, Yubo; Sun, Yi; Wenger, Leonor; Rutter, Joni L.; Brinckerhoff, Constance E.; Cheung, Herman S.

In: Journal of Biological Chemistry, Vol. 274, No. 17, 23.04.1999, p. 11535-11540.

Research output: Contribution to journalArticle

Sun, Yubo ; Sun, Yi ; Wenger, Leonor ; Rutter, Joni L. ; Brinckerhoff, Constance E. ; Cheung, Herman S. / p53 down-regulates human matrix metalloproteinase-1 (collagenase-1) gene expression. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 17. pp. 11535-11540.
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abstract = "Recent studies show that the p53 tumor suppressor protein is overexpressed in rheumatoid arthritis (RA) synovium and that somatic mutations previously identified in human tumors are present in RA synovium (Firestein, G. S., Echeverri, F., Yeo, M., Zvaifler, N. J., and Green, D. R. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 10895-10900; Firestein, G. S., Nguyen, K., Aupperle, K. R., Yeo, M., Boyle, D. L., and Zvaifler, N. J. (1996) Am. J. Pathol. 149, 2143-2151; Reme, T., Travaglio, A., Gueydon, E., Adla, L., Jorgensen, C., and Sany, J. (1998) Clin. Exp. Immunol. 111, 353- 3581). We hypothesize that the abnormality of p53 seen in RA synovium may contribute to joint degeneration through the regulation of human matrix metalloproteinase-1 (hMMP-1, collagenase-1) gene expression. Transcription assays were performed with luciferase reporters driven by the promoter of the hMMP-1 gene or by a minimal promoter containing tandem repeats of the consensus binding sequence for activator protein-1, cotransfected with p53- expressing plasmids. The results revealed that (i) wild-type (wt) p53 down- regulated the promoter activity of hMMP-1 in a dose-dependent fashion; (ii) four of six p53 mutants (commonly found in human cancers) lost this repression activity; and (iii) this p53 repression activity was mediated at least in part by the activator protein-1 sites found in the hMMP-1 promoter. These findings were further confirmed by Northern analysis. The down- regulation of hMMP-1 gene expression by endogenous wt-p53 was shown by treatment of U2-OS cells, a wt-p53-containing osteogenic sarcoma line, and Saos-2 cells, a p53-negative osteogenic sarcoma line, with etoposide, a potent inducer of p53 expression. p53, activated by etoposide, appears to block hMMP-1 promoter activity induced by etoposide in U2-OS cells. In summary, we have shown for the first time that the hMMP-1 gene is a p53 target gene, subject to p53 repression. Because MMP-1 is principally responsible for the irreversible destruction of collagen in articular tissue in RA, abnormality of p53 may contribute to joint degeneration through the regulation of MMP-1 expression.",
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AU - Cheung, Herman S

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