LMP1-Induced Cell Death May Contribute to the Emergency of Its Oncogenic Property

Brocqueville, Guillaume; Ndour, Papa Alioune; Ouk, Tan-Sothéa; Le Goff, Arnaud; De Witte, Caroline; Mougel, Alexandra; Coll, Jean; Fafeur, Véronique; Le Bourhis, Xuefen; Adriaenssens, Eric
April 2013
PLoS ONE;Apr2013, Vol. 8 Issue 4, p1
Academic Journal
Background and Objectives: Epstein-Barr Virus (EBV) Latent Membrane Protein 1 (LMP1) is linked to a variety of malignancies including Hodgkin's disease, lymphomas, nasopharyngeal and gastric carcinoma. LMP1 exerts its transforming or oncogenic activity mainly through the recruitment of intracellular adapters via LMP1 C-terminal Transformation Effector Sites (TES) 1 and 2. However, LMP1 is also reported to elicit significant cytotoxic effects in some other cell types. This cytotoxic effect is quite intriguing for an oncogenic protein, and it is unclear whether both functional aspects of the protein are related or mutually exclusive. Methodology and Principal Findings: Using different ectopic expression systems in both Madin-Darby canine kidney (MDCK) epithelial cells and human embryonic kidney HEK-293 cells, we observe that LMP1 ectopic expression massively induces cell death. Furthermore, we show that LMP1-induced cytotoxicity mainly implies LMP1 C-terminal transformation effector sites and TRADD recruitment. However, stable expression of LMP1 in the same cells, is found to be associated with an increase of cell survival and an acquisition of epithelial mesenchymal transition phenotype as evidenced by morphological modifications, increased cell mobility, increased expression of MMP9 and decreased expression of E-cadherin. Our results demonstrate for the first time that the cytotoxic and oncogenic effects of LMP1 are not mutually exclusive but may operate sequentially. We suggest that in a total cell population, cells resistant to LMP1-induced cytotoxicity are those that could take advantage of LMP1 oncogenic activity by integrating LMP1 signaling into the pre-existent signaling network. Our findings thus reconcile the apparent opposite apoptotic and oncogenic effects described for LMP1 and might reflect what actually happens on LMP1-induced cell transformation after EBV infection in patients.


Related Articles

  • The First Transmembrane Domain of Lipid Phosphatase SAC1 Promotes Golgi Localization. Wang, Jinzhi; Chen, Juxing; Enns, Caroline A.; Mayinger, Peter // PLoS ONE;Aug2013, Vol. 8 Issue 8, p1 

    The lipid phosphatase Sac1 cycles between endoplasmic reticulum and cisternal Golgi compartments. In proliferating mammalian cells, a canonical dilysine motif at the C-terminus of Sac1 is required for coatomer complex-I (COP-I)-binding and continuous retrieval to the ER. Starvation triggers...

  • Early Insights into the Function of KIAA1199, a Markedly Overexpressed Protein in Human Colorectal Tumors. Tiwari, Amit; Schneider, Mirjam; Fiorino, Antonio; Haider, Ritva; Okoniewski, Michal J.; Roschitzki, Bernd; Uzozie, Anuli; Menigatti, Mirco; Jiricny, Josef; Marra, Giancarlo // PLoS ONE;Jul2013, Vol. 8 Issue 7, p1 

    We previously reported that the expression of KIAA1199 in human colorectal tumors (benign and malignant) is markedly higher than that in the normal colonic mucosa. In this study, we investigated the functions of the protein encoded by this gene, which are thus far unknown. Immunostaining studies...

  • Molecular understanding of the slit diaphragm. Grahammer, Florian; Schell, Christoph; Huber, Tobias // Pediatric Nephrology;Oct2013, Vol. 28 Issue 10, p1957 

    Glomerular filtration has always attracted the interest of nephrologists and renal researchers alike. Although several key questions on the structure and function of the kidney filter may have been answered within the last 40 years of intense research, there still remain crucial questions to be...

  • Molecular Signaling Involved in Oxysterol-Induced ß1-Integrin Over-Expression in Human Macrophages. Gargiulo, Simona; Gamba, Paola; Testa, Gabriella; Sottero, Barbara; Maina, Marco; Guina, Tina; Biasi, Fiorella; Poli, Giuseppe; Leonarduzzi, Gabriella // International Journal of Molecular Sciences;Nov2012, Vol. 13 Issue 11, p14278 

    The hypercholesterolemia-atherosclerosis association is now established; hypercholesterolemia may induce vascular-cell activation, subsequently increasing expression of adhesion molecules, cytokines, chemokines, growth factors, and other key inflammatory molecules. Among inflammatory molecules...

  • Rapid Identification of Dysregulated Genes in Cutaneous Malignant Melanoma Metastases Using cDNA Technology. Mirmohammadsadegh, Alireza; Baer, Annett; Nambiar, Sandeep; Bardenheuer, Walter; Hengge, Ulrich R. // Cells Tissues Organs;2004, Vol. 177 Issue 3, p119 

    One important application of DNA microarray technology is the simultaneous analysis of gene expression of different mRNAs. Comparison of mRNA patterns of diseased and healthy tissue may help to understand the pathogenesis of a given disorder. In cancer tissue, identified dysregulated genes may...

  • Widdrol activates DNA damage checkpoint through the signaling Chk2-p53-Cdc25A-p21-MCM4 pathway in HT29 cells. Yun, Hee; Hyun, Sook; Park, Jung; Kim, Byung; Kwon, Hyun // Molecular & Cellular Biochemistry;Apr2012, Vol. 363 Issue 1/2, p281 

    Widdrol is an odorant compound isolated from Juniperus chinensis. We previously reported that widdrol induces Gap 1 (G1) phase cell cycle arrest and leads to apoptosis in human colon adenocarcinoma HT29 cells. It was also reported that this cell cycle arrest is associated with the induction of...

  • An essential role for the Id1/PI3K/Akt/NFkB/survivin signalling pathway in promoting the proliferation of endothelial progenitor cells in vitro. Li, Wei; Wang, Hang; Kuang, Chun-yan; Zhu, Jin-kun; Yu, Yang; Qin, Zhe-xue; Liu, Jie; Huang, Lan // Molecular & Cellular Biochemistry;Apr2012, Vol. 363 Issue 1/2, p135 

    The enhancement of re-endothelialisation is a critical therapeutic option for repairing injured blood vessels. Endothelial progenitor cells (EPCs) are the major source of cells that participate in endothelium repair and contribute to re-endothelialisation by reducing neointima formation after...

  • hTERT Extends the Life of Human Fibroblasts without Compromising Type I Interferon Signaling. Smith, Miles C.; Goddard, Erica T.; Perusina Lanfranca, Mirna; Davido, David J. // PLoS ONE;Mar2013, Vol. 8 Issue 3, p1 

    Primary cells are often used to study viral replication and host-virus interactions as their antiviral pathways have not been altered or inactivated; however, their use is restricted by their short lifespan. Conventional methods to extend the life of primary cultures typically utilize viral...

  • β-Catenin Is Required for the Tumorigenic Behavior of Triple-Negative Breast Cancer Cells. Xu, Jinhua; Prosperi, Jenifer R.; Choudhury, Noura; Olopade, Olufunmilayo I.; Goss, Kathleen H. // PLoS ONE;Feb2015, Vol. 10 Issue 2, p1 

    Our previous data illustrated that activation of the canonical Wnt signaling pathway was enriched in triple-negative breast cancer and associated with reduced overall survival in all patients. To determine whether Wnt signaling may be a promising therapeutic target for triple-negative breast...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics