Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13)
Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13)
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DOI：
10.1074/jbc.275.15.11327
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发表时间：
2000-04-14
影响因子：
4.8
通讯作者：
Cheung, HS
中科院分区：
文献类型：
--
作者：
Sun, YB;Cheung, JM;Cheung, HS
基质金属蛋白酶(MMPs)是一类分泌型或跨膜蛋白家族，可降解细胞外基质中的所有蛋白，与许多异常生理状态有关，包括关节炎和癌症转移。最近，我们首次发现人类的基质金属蛋白酶-1基因是一个受野生型p53抑制的靶基因(Sun，Y.，Sun，Y.I.，Wenger，L.，Rutter，J.L.，Brinckerhoff，C，E.，以及Cheung，H，S.(1999)J.Biol)。11535-11540)中发现：(1)野生型P53、P53-248W、P53-273H和P53-281G过表达可逆转野生型P53突变体对人MMP13基因表达的抑制作用；(3)突变型P53对野生型P53的显性效应似乎是启动子和突变型的特异性效应。一个有趣的发现是，p53突变体P53-281G可以反过来刺激hMMP13的启动子活性2-4倍，并且它比野生型P53更具优势，Northern分析证实了这些发现。虽然这些发现的意义目前尚不清楚，但它们表明，除了细胞因子激活的影响外，hMMP13的基因表达可能在类风湿性关节炎(或癌症)的疾病进展过程中与p53失活有关。由于hMMP13在消化II型胶原方面的活性是hMMP1的5-10倍，因此P53失活导致的MMPI3基因表达失调或上调可能是类风湿关节炎关节退变的原因之一。
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; Iii) 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 MMPI3 gene expression due to the inactivation of p53 may contribute to the joint degeneration in rheumatoid arthritis.