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

Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of China.
Oncogene (Impact Factor: 8.46). 06/2007; 26(21):3069-80. DOI: 10.1038/sj.onc.1210106
Source: PubMed


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-kappaB 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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    • "Interestingly, it has been reported that Epstein-Barr virally encoded protein, latent membrane protein 1 (LMP1) can function to transcriptionally decrease RASSF1A levels and promote tubulin depolymerization and mitotic instability in human epithelial cells (HeLa and HaCaT) [40]. Punctuate structures of tubulin were observed in the cytoplasm indicative of tubulin depolymerization [40]. Decreased RASSF1A levels resulted in increased phosphorylation of IκBα and elevated NFκB activity. "
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    • "Furthermore, β-catenin can also interact with other proteins that have been linked to NPC carcinogenesis including (i) the interleukin-8 (IL-8), the molecule which has been shown to be an angiogenic factor in NPC [39], (ii) the tumor suppressor RAS association family 1A (RASSF1A), in which downregulation causes abnormal mitotic spindles, aneuploidy, and transformation of NPC cells [40], and (iii) E-cadherin, forming a complex with cytoplasmic β-catenin to maintain cellular adhesion [17], mediating cell communication and suppressing metastasis. Lower levels of the cytoplasmic β-catenin in the NPC accelerate the NPC progression and metastasis [18, 26]. "
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    • "Other virus has been shown to induce chromosome aberrations in infected cells [17]. Similarly, LMP1 expression was found to induce aneuploidy in human epithelial cells [25]. Knowing that EBV infection and LMP1 expression induce apoptosis in mammalian cells [6,7], we wanted to answer a further question: is EBV-induced apoptosis a mechanism of chromosome rearrangement in NPC? "
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