Abstract
BackgroundEpstein-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.ResultsIn 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.ConclusionThe 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
Highlights
Epstein-Barr virus (EBV)-encoded LMP1 protein is commonly expressed in nasopharyngeal carcinoma (NPC)
LMP1 suppresses the expression of TFGβ-induced p21 and ATF3 We have found that LMP1 suppresses TGFβ-mediated SMAD transcription without affecting SMAD phosphorylation
LMP1 increases expression of Inhibitor of DNA binding 1 (Id1), a HLH protein whose deregulation plays a role in carcinogenesis and suppresses the activity of Foxo3a transcription factor which is responsible for controlling cell integrity and homeostasis [14,16]
Summary
Epstein-Barr virus (EBV)-encoded LMP1 protein is commonly expressed in nasopharyngeal carcinoma (NPC). 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 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]. A number of Foxo targets have been identified, a recent study in leukemic cells has shown that Foxo3a negatively regulates the transcription of Inhibitor of DNA binding 1 (Id1), a member of the helix-loop-helix (HLH) proteins [6]. The Id1 protein is unable to bind DNA, but it functions as dominant negative regulator, inhibiting the binding of other basic HLH (bHLH) transcription factors to their target genes. Overexpression of Id1 has been observed in a variety of cancers where it may contribute to a variety of cellular functions that include cell proliferation, resistance to apoptosis, angiogenesis, invasion and inhibition of terminal cell differentiation [7]
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