Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-β-induced gene expression
Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-β-induced gene expression
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DOI：
10.1074/jbc.274.38.27161
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发表时间：
1999-09-17
影响因子：
4.8
通讯作者：
Nishida, E
中科院分区：
文献类型：
--
作者：
Hanafusa, H;Ninomiya-Tsuji, J;Nishida, E
转化生长因子-β（TGF-β）激活的激酶1（TAK 1）是丝裂原活化蛋白激酶家族的成员，被认为参与TGF-β诱导的基因表达，但TAK 1到细胞核的信号传导机制在很大程度上仍不清楚。我们已经发现，p38丝裂原活化蛋白激酶及其直接激活剂MKK 6响应于TGF-β而被迅速激活。显性负性MKK 6或显性负性TAK 1的表达抑制TGF-β诱导的转录激活以及p38激活。p38通路的组成性激活：在不存在TGF-β的情况下诱导转录激活，其通过Smad 2和Smad 4的共表达而协同增强，并且通过C-末端截短的显性负性Smad 4的表达而抑制。此外，我们已经发现，激活转录因子-2（ATF-2），其被称为p38的核靶点，响应于TGF-β而在N-末端激活结构域中被磷酸化，ATF-2与Smad 4形成复合物，并且复合物的形成被TGF-β增强。此外，ATF-2的非磷酸化形式的表达抑制TGF-β诱导的转录激活。这些结果表明，p38通路被TGF-β激活，并通过调节Smad介导的通路参与TGF-β诱导的转录激活。
Transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, is suggested to be involved in TGF-beta induced gene expression, but the signaling mechanism from TAK1 to the nucleus remains largely undefined. We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. Expression of dominant negative MKK6 or dominant negative TAK1 inhibited the TGF-beta-induced transcriptional activation as well as the p38 activation. Constitutive activation of the p38 pathway :in the absence of TGF-beta induced the transcriptional activation, which was enhanced synergistically by coexpression of Smad2 and Smad4 and was inhibited by expression of the C-terminal truncated, dominant negative Smad4. Furthermore, we have found that activating transcription factor-2 (ATF-2), which is known as a nuclear target of p38, becomes phosphorylated in the N-terminal activation domain in response to TGF-beta, that ATF-2 forms a complex with Smad4, and that the complex formation is enhanced by TGF-beta. In addition, expression of a nonphosphorylatable form of ATF-2 inhibited the TGF-beta-induced transcriptional activation. These results show that the p38 pathway is activated by TGF-beta and is involved in the TGF-beta-induced transcriptional activation by regulating the Smad-mediated pathway.