Upregulation of Id1 by Epstein-Barr Virus-encoded LMP1 confers resistance to TGFβ-mediated growth inhibition

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 transformationThe Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP1) is commonly expressed in nasopharyngeal carcinoma (NPC) and is believed to play important role in NPC pathogenesis [1]. LMP1 is an oncogenic protein, inducing lymphomagenesis in transgenic mice and transforming rodent fibroblasts in vitro, rendering them tumourigenic in vivo. In vitro studies show that LMP1 is essential for EBV immortalisation of primary B cells, and can induce a state of cell activation in B lymphoma-derived cell lines. In epithelial cells, LMP1 increases cell proliferation, promotes anchorage independent growth, protects cells from apoptosis, induces an epithelial-mesenchymal transformation, promotes cell invasion and perturbs epithelial cell differentiation [2,3]. LMP1 is an integral membrane protein comprising a 24 amino acid N-terminal cytoplasmic domain, six trans