Smad3 mediates transforming growth factor-β-induced collagenase-3 (matrix metalloproteinase-13) expression in human gingival fibroblasts -: Evidence for cross-talk between Smad3 and p38 signaling pathways
Smad3 mediates transforming growth factor-β-induced collagenase-3 (matrix metalloproteinase-13) expression in human gingival fibroblasts -: Evidence for cross-talk between Smad3 and p38 signaling pathways
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DOI：
10.1074/jbc.m206535200
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发表时间：
2002-11-29
影响因子：
4.8
通讯作者：
Kähäri, VM
中科院分区：
文献类型：
--
作者：
Leivonen, SK;Chantry, A;Kähäri, VM
转化生长因子-β（TGF-β）是人牙龈成纤维细胞中胶原酶-3（NIMP-13）基因表达的有效诱导剂，这需要激活p38丝裂原活化蛋白激酶途径。在这里，我们已经构建了重组腺病毒窝藏血凝素标记的Smad 2，Smad 3和Smad 4的基因，并使用这些在解剖的作用Smads，TGF-β的信号介质，在调节内源性MMP-13基因在人牙龈成纤维细胞的表达。腺病毒表达的Smad 3，而不是Smad 2，增强TGF-β诱导的MMP-13表达的诱导。此外，腺病毒介导的显性负性Smad 3基因阻断了TGF-β诱导的牙龈成纤维细胞MMP-13的表达。Smad 3与组成型活性MKK 3b和MKK 6 b（p38的上游激活剂）的共表达导致Smad 3在不存在TGF-β的情况下发生核转位，并诱导MMP-13表达。由Smad 3和MKK 3b或MKK 6 b的组成型活性突变体诱导的MMP-13表达被特异性p38抑制剂SB 203580和p38 α的显性负性形式阻断。这些结果表明，TGF-β诱导的牙龈成纤维细胞中人MMP-13基因的表达依赖于两种不同的信号通路（即Smad 3和p38 α）的激活。此外，这些研究结果提供了一种新型的串扰之间的Smad和p38丝裂原活化蛋白激酶信号级联，其中涉及激活Smad 3的p38 α的证据。
Transforming growth factor-beta (TGF-beta) is a potent inducer of collagenase-3 (NIMP-13) gene expression in human gingival fibroblasts, and this requires activation of the p38 mitogen-activated protein kinase pathway. Here, we have constructed recombinant adenoviruses harboring genes for hemagglutinin-tagged Smad2, Smad3, and Smad4 and used these in dissecting the role of Smads, the signaling mediators of TGF-beta, in regulation of endogenous MMP-13 gene expression in human gingival fibroblasts. Adenoviral expression of Smad3, but not Smad2, augmented the TGF-beta-elicited induction of MMP-13 expression. In addition, adenoviral gene delivery of dominant negative Smad3 blocked the TGF-beta-induced MMP-13 expression in gingival fibroblasts. Co-expression of Smad3 with constitutively active MKK3b and MKK6b, the upstream activators of p38, resulted in nuclear translocation of Smad3 in the absence of TGF-beta and in induction of MMP-13 expression. The induction of MMP-13 expression by Smad3 and constitutively active mutants of MKK3b or MKK6b was blocked by specific p38 inhibitor SB203580 and by the dominant negative form of p38alpha. These results show that TGF-beta-induced expression of human MMP-13 gene in gingival fibroblasts is dependent on the activation of two distinct signaling pathways (i.e. Smad3 and p38alpha). In addition, these findings provide evidence for a novel type of crosstalk between Smad and p38 mitogen-activated protein kinase signaling cascades, which involves activation of Smad3 by p38alpha.