Transforming growth factor-β requires its target plasminogen activator inhibitor-1 for cytostatic activity
Transforming growth factor-β requires its target plasminogen activator inhibitor-1 for cytostatic activity
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DOI：
10.1074/jbc.m803341200
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发表时间：
2008-09-05
影响因子：
4.8
通讯作者：
Bernards, Rene
中科院分区：
文献类型：
--
作者：
Kortlever, Roderik M.;Nijwening, Jeroen H.;Bernards, Rene
细胞因子转化生长因子β（TGF β）在大多数正常细胞中具有强的抗增殖活性，但在肿瘤发生的后期阶段有助于肿瘤进展。目前还不完全清楚哪些TGF β靶基因在因果关系上参与介导其细胞抑制活性。我们在这里报告，抑制TGF β的靶基因编码纤溶酶原激活物抑制剂-1（派-1）的RNA干扰导致逃逸的细胞生长抑制活性的TGF β在人角质形成细胞（HaCaTs）和原代小鼠胚胎成纤维细胞。与此一致，派-1敲除小鼠胚胎成纤维细胞也对TGF β生长停滞具有抗性。相反，我们表明，派-1在增殖HaCaT细胞异位表达诱导生长停滞。派-1敲除不干扰典型的TGF β信号传导，如通过SMAD磷酸化和真正的TGF β靶基因的诱导所判断的。相反，派-1的敲低导致蛋白激酶B的持续活化。值得注意的是，我们发现，组成性蛋白激酶B活性导致逃避TGF β的生长抑制作用。我们的数据与TGF β诱导派-1对诱导增殖停滞至关重要的模型一致。
The cytokine transforming growth factor beta(TGF beta) has strong antiproliferative activity in most normal cells but contributes to tumor progression in the later stages of oncogenesis. It is not fully understood which TGF beta target genes are causally involved in mediating its cytostatic activity. We report here that suppression of the TGF beta target gene encoding plasminogen activator inhibitor-1 (PAI-1) by RNA interference leads to escape from the cytostatic activity of TGF beta both in human keratinocytes (HaCaTs) and primary mouse embryo fibroblasts. Consistent with this, PAI-1 knock-out mouse embryo fibroblasts are also resistant to TGF beta growth arrest. Conversely, we show that ectopic expression of PAI-1 in proliferating HaCaT cells induces a growth arrest. PAI-1 knockdown does not interfere with canonical TGF beta signaling as judged by SMAD phosphorylation and induction of bona fide TGF beta target genes. Instead, knockdown of PAI-1 results in sustained activation of protein kinase B. Significantly, we find that constitutive protein kinase B activity leads to evasion of the growth-inhibitory action of TGF beta. Our data are consistent with a model in which induction of PAI-1 by TGF beta is critical for the induction of proliferation arrest.