Wild Type and Mutant p53 Differentially Regulate the Gene Expression of Human Collagenase-3 (hMMP-13)

Abstract

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. Rheumatoid arthritis (RA)1 is a systemic disease of unknown etiology characterized by severe inflammation, abnormal immune response, synovial hyperplasia, and extensive destruction of the articular cartilage (2). The progressive destruction of articular cartilage in RA is partly mediated by matrix metalloproteinases (MMPs) (3, 4). Collagenase-1 (MMP-1), stromelysin (MMP-3), gelatinase A and B (MMP-2 and MMP-9), and collagenase-3 (MMP-13) are all present at significantly elevated levels in cartilage, synovial membranes, and synovial fluid of patients with RA (5-7). MMP-13, a newly discovered human collagenase (6 -9), besides cleaving type II collagen more efficiently than MMP-1 (10), is also active against aggrecan, the major proteoglycan of the hyaline articular cartilage (11). Therefore, it has been suggested that MMP-13 may represent a particularly significant mediator of tissue destruction in arthritis. The p53 tumor suppressor gene has been implicated in the malignant progression of cancers, and the mutational inactivation of p53 is the most frequent genetic alteration in human cancers. Recent studies have linked this powerful tumor suppressor to RA. It has been demonstrated independently by two groups that p53 protein is overexpressed in RA synovium and in synoviocytes cultured from RA patients (12,14), and that mutant p53 transcripts previously identified in human tumors are present in these tissues and cells (13,14).p53 is a transcription factor that recognizes a specific consensus DNA sequence consisting of two copies of a 10-base pair motif, 5Ј-RRRC(A/T)(T/A)GYYY-3Ј (where R indicates a purine nucleoside and Y indicates a pyrimidine nucleoside)...

Functional Significance of Metastasis-inducing S100A4(Mts1) in Tumor-Stroma Interplay

“…2 Additionally, simultaneous activation/stabilization of p53 and increase of the proteolytic activity are demonstrated here. Together, these results support our assumption of the possible implication of these transcription factors in S100A4-mediated proteinase activation, which is in good agreement with the data on their tight implication in the transcriptional regulation of MMPs (47)(48)(49).…”

RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome

“…For example, the promoter of the gene encoding the insulin-like growth factor I receptor is repressed by wild-type p53 but stimulated by certain tumour-derived p53 mutants (Werner et al, 1996). Similar observations have been reported for the gene encoding matrix metalloproteinase-13 (Sun et al, 2000).…”

“…It can bind to DNA in a sequence-speci®c fashion and stimulate expression of proximal genes (Bargonetti et al, 1991;Farmer et al, 1992;Kern et al, 1991;. As well as activating genes with p53-binding sites, p53 is also able to repress promoters that lack its response element (Cairns and White, 1998;Chesnokov et al, 1996;Crook et al, 1994;Farmer et al, 1996;Ginsberg et al, 1991;Horikoshi et al, 1995;Kley et al, 1992;Mack et al, 1993;Mercer et al, 1991;Ragimov et al, 1993;Santhanam et al, 1991;Seto et al, 1992;Subler et al, 1992;Sun et al, 2000;Venkatachalam et al, 1998;Werner et al, 1996;Yu et al, 1999;Zhao et al, 2000). Although such repression occurs in the absence of a DNA site that is bound directly by p53, it is nevertheless highly speci®c; microarray analysis of *6000 genes showed that only 0.9% were inhibited by p53, whilst 1.8% were induced (Zhao et al, 2000).…”

p53, secreted by K-Ras–Snail pathway, is endocytosed by K-Ras-mutated cells; implication of target-specific drug delivery and early diagnostic marker

“…These results suggested that secreted p53 would be digested not only by serine protease but also by other kinds of proteases, such as MMP (Figure 4d). As p53 suppresses MMPs at the transcription level (Sun et al, 2000), secreted p53 might be easily digested by elevated MMPs. However, more details can be revealed by further investigation.…”