Upregulation of Id1 by Epstein-Barr virus-encoded LMP1 confers resistance to TGFbeta-mediated growth inhibition.
Upregulation of Id1 by Epstein-Barr virus-encoded LMP1 confers resistance to TGFbeta-mediated growth inhibition.
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DOI：
10.1186/1476-4598-9-155
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发表时间：
2010-06-18
期刊：
影响因子：
37.3
通讯作者：
Young LS
中科院分区：
文献类型：
--
作者：
Lo AK;Dawson CW;Lo KW;Yu Y;Young LS
EB病毒编码的LMP1蛋白在鼻咽癌中普遍表达。鉴于LMP1能够激活多条信号通路并改变各种下游靶点的表达和活性，因此LMP1是推动肿瘤发生的最佳候选基因。对转化生长因子β介导的细胞停滞的抵抗是LMP1的生长转化作用之一。在LMP1操纵的下游靶点中，Id1的诱导和Foxo3a的失活似乎与LMP1介导的效应特别相关。Id1是HLH蛋白，参与细胞转化和细胞增殖，而转录因子Foxo3a通过调节细胞凋亡来控制细胞完整性和动态平衡。LMP1诱导这些效应的机制(S)还没有完全被描述。在这项研究中，我们证明了LMP1诱导Foxo3a磷酸化和失活的能力与Id1的上调有关。此外，我们发现Id1的诱导对于LMP1的转化功能是必不可少的，因为Id1的过表达促进了细胞的增殖，减弱了转化生长因子β-sMAD介导的转录，并使细胞对转化生长因子β介导的细胞停滞产生抵抗。在表达LMP1的上皮细胞中，Id1的沉默取消了LMP1对转化生长因子β介导的细胞生长停滞的抑制作用，并降低了LMP1抑制SMAD转录活性的能力。作为对转化生长因子β刺激的反应，LMP1不会取消SMAD的磷酸化，但会抑制p21蛋白的表达。此外，我们还发现在转化生长因子β刺激表达LMP1的细胞中可以诱导Id1的表达。我们提供的证据表明，LMP1抑制转录抑制因子ATF3，可能导致转化生长因子β诱导的Id1上调。目前的数据提供了关于lmp1抑制转化生长因子β诱导的细胞停滞的新机制的新信息，强调了ld1在lmp1介导的细胞转化中的重要性。
Epstein-Barr virus (EBV)-encoded LMP1 protein is commonly expressed in nasopharyngeal carcinoma (NPC). LMP1 is a prime candidate for driving tumourigenesis given its ability to activate multiple signalling pathways and to alter the expression and activity of variety of downstream targets. Resistance to TGFβ-mediated cytostasis is one of the growth transforming effects of LMP1. Of the downstream targets manipulated by LMP1, the induction of Id1 and inactivation of Foxo3a appear particularly relevant to LMP1-mediated effects. Id1, a HLH protein is implicated in cell transformation and plays a role in cell proliferation, whilst Foxo3a, a transcription factor controls cell integrity and homeostasis by regulating apoptosis. The mechanism(s) by which LMP1 induces these effects have not been fully characterised. In this study, we demonstrate that the ability of LMP1 to induce the phosphorylation and inactivation of Foxo3a is linked to the upregulation of Id1. Furthermore, we show that the induction of Id1 is essential for the transforming function of LMP1 as over-expression of Id1 increases cell proliferation, attenuates TGFβ-SMAD-mediated transcription and renders cells refractory to TGFβ-mediated cytostasis. Id1 silencing in LMP1-expressing epithelial cells abolishes the inhibitory effect of LMP1 on TGFβ-mediated cell growth arrest and reduces the ability of LMP1 to attenuate SMAD transcriptional activity. In response to TGFβ stimulation, LMP1 does not abolish SMAD phosphorylation but inhibits p21 protein expression. In addition, we found the induction of Id1 in LMP1-expressing cells upon stimulation by TGFβ. We provide evidence that LMP1 suppresses the transcriptional repressor ATF3, possibly leading to the TGFβ-induced Id1 upregulation. The current data provide novel information regarding the mechanisms by which LMP1 suppresses TGFβ-induced cytostasis, highlighting the importance of Id1 in LMP1 mediated cell transformation
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