Smad-dependent GADD45beta expression mediates delayed activation of p38 MAP kinase by TGF-beta.
Smad-dependent GADD45beta expression mediates delayed activation of p38 MAP kinase by TGF-beta.
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发表时间：
2002
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通讯作者：
M. Takekawa;K. Tatebayashi;F. Itoh;M. Adachi;K. Imai;H. Saito
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作者：
M. Takekawa;K. Tatebayashi;F. Itoh;M. Adachi;K. Imai;H. Saito
转化生长因子-β（TGF-β）在与其特异性受体结合时，通过磷酸化激活转录因子Smad。TGF-β也激活p38 MAPK通路，但早期p38激活和延迟p38激活似乎存在不同的机制。在这份报告中，我们证明，Smad依赖的GADD 45 β的表达是负责延迟激活p38的TGF-β。GADD 45 β蛋白结合并激活MTK 1（= MEKK 4），MTK 1是MAPKKK家族激酶的成员，也是p38 MAPK级联的上游激活剂。TGF-β诱导的GADD 45 β表达和延迟的p38激活都需要功能性Smad蛋白。反义抑制GADD 45 β表达可抑制TGF-β诱导的延迟p38激活，而过表达GADD 45 β可通过MTK 1激活p38 MAPK。TGF-β通过Smad依赖性p38激活诱导血管生成抑制剂血小板反应蛋白-1（TSP-1）的表达。因此，TGF-β诱导的p38激活，介导的GADD 45 β表达，可能发挥重要作用的TGF-β的生物学效应。
Transforming growth factor-beta (TGF-beta), when bound to its specific receptor, activates the transcription factor Smad by phosphorylation. TGF-beta also activates the p38 MAPK pathway, but there seem to be disparate mechanisms for the early p38 activation and delayed p38 activation. In this report, we demonstrate that Smad-dependent expression of GADD45beta is responsible for the delayed activation of p38 by TGF-beta. The GADD45beta protein binds and activates MTK1 (= MEKK4), which is a member of the MAPKKK family kinases and an upstream activator of the p38 MAPK cascade. Both TGF-beta-induced GADD45beta expression and the delayed p38 activation require functional Smad proteins. Antisense inhibition of GADD45beta expression suppresses the TGF-beta-induced delayed p38 activation, whereas overexpression of GADD45beta activates the p38 MAPK via MTK1. Expression of the angiogenesis inhibitor thrombospondin-1 (TSP-1) is induced by TGF-beta via Smad-dependent p38 activation. Thus TGF-beta-induced p38 activation, mediated by GADD45beta expression, may play an important role in the biological effects of TGF-beta.