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Abstract：
Interferon consensus sequence binding protein (ICSBP), also known as interferon regulatory factor (IRF)-8, is a member of the interferon (IFN)-γ regulatory transcription factors. Studies have suggested a connection between TGF-β signaling and IRFs. Thus, we investigated the effect of ICSBP on transforming growth factor (TGF)-β signaling in HL-60, an acute promyelocytic leukemia cell line. Stable expression of ICSBP in HL-60 cells resulted in strong induction of TGF-β receptor expression and activation of non-Smad as well as Smad pathways. ICSBP expression also augmented cell growth. ICSBP knockdown with small interfering RNA (siRNA) attenuated cell growth and decreased TGF-β receptor I (TGF-βRI) expression. In addition, reduction of TGF-βRI using siRNA or pharmacological inhibitor reduced growth of ICSBP-expressing cells. ICSBP expression also led to increased phosphorylation and activation of Akt and p38 MAPK. However, p38 MAPK, but not PI3K-Akt, inhibition abrogated ICSBP-mediated proliferation. Furthermore, siRNA knockdown of either ICSBP or TGF-βRI resulted in decreased p38 activation. Intriguingly, TGF-β-activated kinase 1 (TAK-1), which phosphorylates p38, was activated in ICSBP-expressing cells and its activity was reduced by TGF-βRI inhibition. Finally, siRNA knockdown of ICSBP or TGF-βRI reduced TAK-1 phosphorylation. This study identifies a novel role for ICSBP in regulating cell growth via TGF-β receptor upregulation and subsequent activation of the TGF-β receptor/TAK-1/p38 pathway.
摘要：
干扰素共有序列结合蛋白(ICSBP),也称为干扰素调节因子(IRF)-8,是干扰素(IFN)-γ调节转录因子的成员。研究表明TGF-β信号传导与IRF之间存在联系。因此，我们研究了ICSBP对急性早幼粒细胞白血病细胞系HL-60中转化生长因子（TGF）-β信号传导的影响。ICSBP在HL-60细胞中的稳定表达导致TGF-β受体表达的强烈诱导和非Smad以及Smad途径的激活。ICSBP表达也增强了细胞生长。用小干扰RNA(siRNA)敲除ICSBP减弱细胞生长并降低TGF-β受体I(TGF-βRI)表达。此外,使用siRNA或药物抑制剂减少TGF-βRI降低ICSBP表达细胞的生长。ICSBP表达还导致Akt和p38MAPK的磷酸化和活化增加。然而,p38MAPK,但不是PI3K-Akt，抑制消除ICSBP介导的增殖。此外，ICSBP或TGF-βRI的siRNA敲低导致p38活化降低。有趣的是，TGF-β活化激酶1(TAK-1),在表达ICSBP的细胞中磷酸化p38被激活，其活性被TGF-βRI抑制降低。最后,ICSBP或TGF-βRI的siRNA敲低降低了TAK-1磷酸化。这项研究确定了ICSBP在通过TGF-β受体上调和随后激活TGF-β受体/TAK-1/p38途径调节细胞生长中的新作用。
