Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13).
Matrix metalloproteinases (MMPs) are a family of secreted or transmembrane proteins that can degrade all the proteins of the extracellular matrix and have been implicated in many abnormal physiological conditions including arthritis and cancer metastasis. Recently we have shown for the first time that the human MMP-1 gene is a p53 target gene subject to repression by wild type p53 (Sun, Y., Sun, Y. I., Wenger, L., Rutter, J. L., Brinckerhoff, C. E., and Cheung, H. S. (1999) J. Biol. Chem. 274, 11535-11540). Here, we report that cotransfection of fibroblast-like synoviocytes with p53 expression and hMMP13CAT reporter plasmids revealed that (i) hMMP13, another member of the human MMP family, was down-regulated by wild type p53, whereas all six of the p53 mutants tested lost the wild type p53 repressor activity in fibroblast-like synoviocytes; (ii) this repression of hMMP-13 gene expression by wild type p53 could be reversed by overexpression of p53 mutants p53-143A, p53-248W, p53-273H, and p53-281G; (iii) the dominant effect of p53 mutants over wild type p53 appears to be a promoter- and mutant-specific effect. An intriguing finding was that p53 mutant p53-281G could conversely stimulate the promoter activity of hMMP13 up to 2-4-fold and that it was dominant over wild type p53. Northern analysis confirmed these findings. Although the significance of these findings is currently unknown, they suggest that in addition to the effect of cytokines activation, the gene expression of hMMP13 could be dysregulated during the disease progression of rheumatoid arthritis (or cancer) associated with p53 inactivation. Since hMMP13 is 5-10 times as active as hMMP1 in its ability to digest type II collagen, the dysregulation or up-modulation of MMP13 gene expression due to the inactivation of p53 may contribute to the joint degeneration in rheumatoid arthritis.
Sun
Y
Y
Department of Medicine, University of Miami School of Medicine, Miami, Florida 33101, USA.
Cheung
J M
JM
Martel-Pelletier
J
J
Pelletier
J P
JP
Wenger
L
L
Altman
R D
RD
Howell
D S
DS
Cheung
H S
HS
D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000235:genetics; D017364:Collagenases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053509:Matrix Metalloproteinase 13; D009154:Mutation; D011401:Promoter Regions, Genetic; D020218:Response Elements; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13