Lo, Angela K. F., Dawson, Christopher W., Lo, Kwok W., Yu, Yanxing and Young, Lawrence S. (2010) Upregulation of Id1 by Epstein-Barr Virus-encoded LMP1 confers resistance to TGFβ-mediated growth inhibition. Molecular Cancer, Vol.9 (No.1). p. 155. doi:10.1186/1476-4598-9-155 ISSN 1476-4598.
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Abstract
Background
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.
Results
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.
Conclusion
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.
| Item Type: | Journal Article |
|---|---|
| Subjects: | Q Science > QR Microbiology > QR355 Virology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
| Library of Congress Subject Headings (LCSH): | Epstein-Barr virus -- Genetic aspects, Pharynx -- Cancer -- Pathogenesis |
| Journal or Publication Title: | Molecular Cancer |
| Publisher: | BioMed Central Ltd. |
| ISSN: | 1476-4598 |
| Official Date: | 18 June 2010 |
| Dates: | Date Event 18 June 2010 Published |
| Volume: | Vol.9 |
| Number: | No.1 |
| Page Range: | p. 155 |
| DOI: | 10.1186/1476-4598-9-155 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Open Access (Creative Commons open licence) |
| Date of first compliant deposit: | 23 December 2015 |
| Date of first compliant Open Access: | 23 December 2015 |
| Funder: | Cancer Research UK (CRUK), Chinese University of Hong Kong. Li Ka Shing Institute of Health Sciences, Kadoorie Charitable Foundation |
| URI: | https://wrap.warwick.ac.uk/51855/ |
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