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首页> 外文期刊>Molecular biology of the cell >Transforming growth factor-beta 1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3
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Transforming growth factor-beta 1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3

机译：转化生长因子-beta 1（TGF-beta）诱导的前列腺癌细胞凋亡涉及TGF-beta激活的激酶1和有丝分裂原激活的蛋白激酶3的Smad7依赖性激活p38。

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摘要

The inhibitory Smad7, a direct target gene for transforming growth factor-beta (TGF-beta), mediates TGF-beta1-induced apoptosis in several cell types. Herein, we report that apoptosis of human prostate cancer PC-3U cells induced by TGF-beta1 or Smad7 overexpression is caused by a specific activation of the p38 mitogen-activated protein kinase pathway in a TGF-beta-activated kinase 1 (TAK1)- and mitogen-activated protein kinase kinase 3 (MKK3)-dependent manner. Expression of dominant negative p38, dominant negative MKK3, or incubation with the p38 selective inhibitor [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], prevented TGF-beta1-induced apoptosis. The expression of Smad7 was required for TGF-beta-induced activation of MKK3 and p38 kinases, and endogenous Smad7 was found to interact with phosphorylated p38 in a ligand-dependent manner. Ectopic expression of wild-type TAK1 promoted TGF-beta1-induced phosphorylation of p38 and apoptosis, whereas dominant negative TAK1 reduced TGF-beta1-induced phosphorylation of p38 and apoptosis. Endogenous Smad7 was found to interact with TAK1, and TAK1, MKK3, and p38 were coimmunoprecipitated with Smad7 in transiently transfected COS1 cells. Moreover, ectopically expressed Smad7 enhanced the coimmunoprecipitation of HA-MKK3 and Flag-p38, supporting the notion that Smad7 may act as a scaffolding protein and facilitate TAK1- and MKK3-mediated activation of p38. [References: 65]
机译：抑制性Smad7是转化生长因子-β（TGF-β）的直接靶基因，可介导TGF-β1诱导的几种细胞类型的凋亡。在此，我们报道了由TGF-beta1或Smad7过表达诱导的人类前列腺癌PC-3U细胞凋亡是由TGF-beta激活的激酶1（TAK1）-中p38丝裂原激活的蛋白激酶途径的特异性激活引起的和有丝分裂原激活的蛋白激酶激酶3（MKK3）依赖方式。表达显性阴性p38，显性阴性MKK3或与p38选择性抑制剂[4-（4-氟苯基）-2-（4-甲基亚磺酰基苯基）-5-（4-吡啶基）1H-咪唑]孵育可防止TGF-beta1诱导的细胞凋亡。 Smad7的表达是TGF-β诱导的MKK3和p38激酶激活所必需的，并且发现内源性Smad7以依赖配体的方式与磷酸化的p38相互作用。野生型TAK1的异位表达促进TGF-β1诱导的p38磷酸化和细胞凋亡，而显性负TAK1降低TGF-β1诱导的p38的磷酸化和细胞凋亡。发现内源性Smad7与TAK1相互作用，并且TAK1，MKK3和p38在瞬时转染的COS1细胞中与Smad7共免疫沉淀。此外，异位表达的Smad7增强了HA-MKK3和Flag-p38的共免疫沉淀，支持了Smad7可以充当支架蛋白并促进TAK1和MKK3介导的p38活化的观点。 [参考：65]

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