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Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells

Oncogene volume 26, pages 3069–3080 (2007)Cite this article

Abstract

Epstein–Barr virus (EBV) infection is closely associated with nasopharyngeal carcinoma (NPC) and can be detected in early premalignant lesions of nasopharyngeal epithelium. The latent membrane protein 1 (LMP1) is an oncoprotein encoded by the EBV and is believed to play a role in transforming premalignant nasopharyngeal epithelial cells into cancer cells. RASSF1A is a tumor-suppressor gene commonly inactivated in many types of human cancer including NPC. In this study, we report a novel function of LMP1, in down-regulating RASSF1A expression in human epithelial cells. Downregulation of RASSF1A expression by LMP1 is dependent on the activation of intracellular signaling of NF-κB involving the C-terminal activating regions (CTARs) of LMP1. LMP1 expression also suppresses the transcriptional activity of the RASSF1A core promoter. RASSF1A stabilizes microtubules and regulates mitotic events. Aberrant mitotic spindles and chromosome aberrations are reported phenotypes in RASSF1A inactivated cells. In this study, we observed that LMP1 expression in human epithelial cells could induce aberrant mitotic spindles, disorganized interphase microtubules and aneuploidy. LMP1 expression could also suppress microtubule dynamics as exemplified by tracking movements of the growing tips of microtubules in live cells by transfecting EGFP-tagged EB1 into cells. The aberrant mitotic spindles and interphase microtubule organization induced by LMP1 could be rescued by transfecting RASSF1A expression plasmid into cells. Downregulation of RASSF1A expression by LMP1 may facilitate its role in transformation of premalignant nasopharyngeal epithelial cells into cancer cells.

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Acknowledgements

This project was supported by the research Grant council, Hong Kong (Grant numbers: HKU7356/02M, N_HKU728/04, HKU7 and CRCG 10205784). We also acknowledged the support from the Core Imaging Facility of the Li Ka Shing Faculty of Medicine, University of Hong Kong for the live cell imaging study.

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Authors and Affiliations

  1. Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of China

    C Man, A L M Cheung & S W Tsao

  2. Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of China

    Y L Kwong

  3. Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of China

    D Y Jin

  4. Department of Zoology, Faculty of Science, The University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of China

    L T O Lee, V H Y Lee & B K C Chow

  5. Department of Cellular and Anatomical Pathology, Chinese University of Hong Kong, Shatin, Hong Kong SAR, People's Republic of China

    K W Lo

  6. Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    J Rosa & S Doxsey

  7. Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, People's Republic of China

    Z G Wu

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  1. C Man
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Correspondence to S W Tsao.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Man, C., Rosa, J., Lee, L. et al. Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells. Oncogene 26, 3069–3080 (2007). https://doi.org/10.1038/sj.onc.1210106

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