Westermarck J, Li S P, Kallunki T, Han J, Kähäri V M
Turku Centre for Biotechnology, University of Turku, University of Turku, FIN-20520 Turku, Finland.
Mol Cell Biol. 2001 Apr;21(7):2373-83. doi: 10.1128/MCB.21.7.2373-2383.2001.
Degradation of collagenous extracellular matrix by collagenase 1 (also known as matrix metalloproteinase 1 [MMP-1]) plays a role in the pathogenesis of various destructive disorders, such as rheumatoid arthritis, chronic ulcers, and tumor invasion and metastasis. Here, we have investigated the role of distinct mitogen-activated protein kinase (MAPK) pathways in the regulation of MMP-1 gene expression. The activation of the extracellular signal-regulated kinase 1 (ERK1)/ERK2 (designated ERK1,2) pathway by oncogenic Ras, constitutively active Raf-1, or phorbol ester resulted in potent stimulation of MMP-1 promoter activity and mRNA expression. In contrast, activation of stress-activated c-Jun N-terminal kinase and p38 pathways by expression of constitutively active mutants of Rac, transforming growth factor beta-activated kinase 1 (TAK1), MAPK kinase 3 (MKK3), or MKK6 or by treatment with arsenite or anisomycin did not alone markedly enhance MMP-1 promoter activity. Constitutively active MKK6 augmented Raf-1-mediated activation of the MMP-1 promoter, whereas active mutants of TAK1 and MKK3b potently inhibited the stimulatory effect of Raf-1. Activation of p38 MAPK by arsenite also potently abrogated stimulation of MMP-1 gene expression by constitutively active Ras and Raf-1 and by phorbol ester. Specific activation of p38alpha by adenovirus-delivered constitutively active MKK3b resulted in potent inhibition of the activity of ERK1,2 and its upstream activator MEK1,2. Furthermore, arsenite prevented phorbol ester-induced phosphorylation of ERK1,2 kinase-MEK1,2, and this effect was dependent on p38-mediated activation of protein phosphatase 1 (PP1) and PP2A. These results provide evidence that activation of signaling cascade MKK3-MKK3b-->p38alpha blocks the ERK1,2 pathway at the level of MEK1,2 via PP1-PP2A and inhibits the activation of MMP-1 gene expression.
胶原酶1（也称为基质金属蛋白酶1 [MMP-1]）对胶原细胞外基质的降解在多种破坏性疾病的发病机制中起作用，如类风湿性关节炎、慢性溃疡以及肿瘤侵袭和转移。在此，我们研究了不同的丝裂原活化蛋白激酶（MAPK）途径在MMP-1基因表达调控中的作用。致癌性Ras、组成型活性Raf-1或佛波酯对细胞外信号调节激酶1（ERK1）/ERK2（称为ERK1,2）途径的激活导致MMP-1启动子活性和mRNA表达的强烈刺激。相反，通过Rac组成型活性突变体、转化生长因子β激活激酶1（TAK1）、MAPK激酶3（MKK3）或MKK6的表达或通过亚砷酸盐或茴香霉素处理来激活应激激活的c-Jun N端激酶和p38途径，单独并不会显著增强MMP-1启动子活性。组成型活性MKK6增强了Raf-1介导的MMP-1启动子激活，而TAK1和MKK3b的活性突变体则强烈抑制Raf-1的刺激作用。亚砷酸盐对p38 MAPK的激活也有效消除了组成型活性Ras和Raf-1以及佛波酯对MMP-1基因表达的刺激。腺病毒递送的组成型活性MKK3b对p38α的特异性激活导致ERK1,2及其上游激活剂MEK1,2的活性受到强烈抑制。此外，亚砷酸盐阻止了佛波酯诱导的ERK1,2激酶-MEK1,2的磷酸化，并且这种作用依赖于p38介导的蛋白磷酸酶1（PP1）和PP2A的激活。这些结果证明，信号级联MKK3-MKK3b→p38α的激活通过PP1-PP2A在MEK1,2水平阻断ERK1,2途径，并抑制MMP-1基因表达的激活。
