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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: 8.56). 06/2007; 26(21):3069-80. DOI: 10.1038/sj.onc.1210106
Source: PubMed

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-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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    • "A tumor suppressor gene RASSF1A is known to stabilize cellular microtubules and regulate mitotic events, and its inactivation induces abnormal spindle formation and chromosomal instability (Liu et al., 2003;Rong et al., 2004). EBV LMP1 has been found to down-regulate the expression of RASSF1A through an NF-κB pathway, resulting in aberrant mitotic spindles and aneuploid chromosomes (Man et al., 2007) (Table 1). In addition, latent EBV infection impairs the mitotic SAC and rescues Burkitt's lymphoma-derived cells from other caspase-dependent cell death when cultured in vitro (Leao et al., 2007). "
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    • "The above-mentioned findings were confirmed in a telomerase immortalized RPEhTert epithelial cells stably expressing GFP-␣-tubulin, previously used in our microtubule studies (Rosa et al., 2006; Man et al., 2007). Exogenous expression of Id1 in RPEhTert cells also induced abnormal interphase microtubules and monopolar mitotic spindles (Figure 2C), compared with the network-like microtubules in the control Figure 1 (cont). "
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