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

Area of Science:

• Molecular Biology
• Rheumatology
• Oncology

Background:

• Rheumatoid arthritis (RA) synovium shows overexpression of the p53 tumor suppressor protein.
• Somatic mutations of p53, typically found in human tumors, are also present in RA synovium.
• The role of p53 abnormalities in RA pathogenesis, particularly in joint degeneration, remains unclear.

Purpose of the Study:

• To investigate the hypothesis that p53 abnormalities in RA synovium contribute to joint degeneration.
• To determine if p53 regulates the expression of human matrix metalloproteinase-1 (hMMP-1), also known as collagenase-1.
• To elucidate the mechanism by which p53 influences hMMP-1 gene expression.

Main Methods:

• Luciferase reporter assays were used to measure hMMP-1 promoter activity.
• Reporter constructs were driven by the hMMP-1 promoter or a minimal promoter with activator protein-1 (AP-1) binding sites.
• Experiments involved co-transfection with p53-expressing plasmids (wild-type and mutant) and treatment with etoposide to induce p53 expression.

Main Results:

• Wild-type p53 dose-dependently down-regulated hMMP-1 promoter activity.
• Four of six cancer-associated p53 mutants lost the ability to repress hMMP-1 promoter activity.
• p53-mediated repression of hMMP-1 was partly dependent on AP-1 binding sites within the promoter.
• Etoposide treatment induced p53 expression and repressed hMMP-1 promoter activity in cells with wild-type p53, but not in p53-negative cells.

Conclusions:

• The human matrix metalloproteinase-1 (hMMP-1) gene is identified as a novel p53 target gene.
• Wild-type p53 represses hMMP-1 gene expression, while common p53 mutants lose this function.
• p53 abnormalities in rheumatoid arthritis synovium may contribute to joint degeneration by altering MMP-1 expression and subsequent collagen destruction.