Epstein‐Barr virus latent membrane 2A (LMP2A) down‐regulates telomerase reverse transcriptase (hTERT) in epithelial cell lines

The latent membrane protein (LMP) 2A, one of the membrane‐spanning polypeptides encoded by the Epstein‐Barr virus (EBV), has been implicated in the maintenance of viral latency and appears to function in part by inhibiting B‐cell receptor (BCR) signaling through its ITAM motifs. It has also been suggested that LMP2A is involved in tumorigenesis mediated by EBV. In our study, we determined regulatory effects of LMP2A on the telomerase reverse transcriptase (hTERT) expression. We observed a significant and constant reduction of hTERT mRNA accompanied by decreased telomerase activity in epithelial cells expressing LMP2A. It was further shown that LMP2A inhibited the hTERT promoter activity in transient transfections of both B cells and epithelial cells, and that the ITAM motif was required for this inhibition. Thus LMP2A expression leads to the transcriptional repression of the hTERT gene through specific pathways, which may thereby contribute to the control of EBV‐latency.

[1]  J. Shay,et al.  Human Telomerase and Its Regulation , 2002, Microbiology and Molecular Biology Reviews.

[2]  Robert A. Weinberg,et al.  Telomerase contributes to tumorigenesis by a telomere length-independent mechanism , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. Choe,et al.  Human Papillomavirus E2 Down-regulates the Human Telomerase Reverse Transcriptase Promoter* , 2002, The Journal of Biological Chemistry.

[4]  E. Robertson,et al.  The Latency-associated Nuclear Antigen of Kaposi's Sarcoma-associated Herpesvirus Transactivates the Telomerase Reverse Transcriptase Promoter* , 2001, The Journal of Biological Chemistry.

[5]  M. Björkholm,et al.  Real-time quantitative telomeric repeat amplification protocol assay for the detection of telomerase activity. , 2001, Clinical chemistry.

[6]  F. Giancotti,et al.  Tyrosine Phosphorylation of the β4 Integrin Cytoplasmic Domain Mediates Shc Signaling to Extracellular Signal-regulated Kinase and Antagonizes Formation of Hemidesmosomes* , 2001, The Journal of Biological Chemistry.

[7]  L. Yoo,et al.  Determining the Role of the Epstein-Barr Virus Cp EBNA2-Dependent Enhancer during the Establishment of Latency by Using Mutant and Wild-Type Viruses Recovered from Cottontop Marmoset Lymphoblastoid Cell Lines , 2000, Journal of Virology.

[8]  J. Sample,et al.  Latent Membrane Protein 2A-Mediated Effects on the Phosphatidylinositol 3-Kinase/Akt Pathway , 2000, Journal of Virology.

[9]  K. M. Bendt,et al.  Epstein-Barr Virus LMP2A Transforms Epithelial Cells, Inhibits Cell Differentiation, and Activates Akt , 2000, Journal of Virology.

[10]  Tony Pawson,et al.  Latent Membrane Protein 2A of Epstein-Barr Virus Binds WW Domain E3 Protein-Ubiquitin Ligases That Ubiquitinate B-Cell Tyrosine Kinases , 2000, Molecular and Cellular Biology.

[11]  R. DePinho,et al.  Cellular Senescence Minireview Mitotic Clock or Culture Shock? , 2000, Cell.

[12]  R. Longnecker,et al.  The Epstein-Barr virus latent membrane protein 2A PY motif recruits WW domain-containing ubiquitin-protein ligases. , 2000, Virology.

[13]  Robert A. Weinberg,et al.  Creation of human tumour cells with defined genetic elements , 1999, Nature.

[14]  M. Björkholm,et al.  Suppression of telomerase reverse transcriptase (hTERT) expression in differentiated HL-60 cells: regulatory mechanisms , 1999, British Journal of Cancer.

[15]  R. Ambinder,et al.  Expression of Epstein-Barr virus BamHI-A rightward transcripts in latently infected B cells from peripheral blood. , 1999, Blood.

[16]  E. Kremmer,et al.  Tyrosine 112 of Latent Membrane Protein 2A Is Essential for Protein Tyrosine Kinase Loading and Regulation of Epstein-Barr Virus Latency , 1998, Journal of Virology.

[17]  P. Pisa,et al.  Telomerase activity and the expression of telomerase components in acute myelogenous leukaemia , 1998, British journal of haematology.

[18]  S. Anderson,et al.  Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. , 1998, Immunity.

[19]  Bernd Wollscheid,et al.  SLP-65: A New Signaling Component in B Lymphocytes which Requires Expression of the Antigen Receptor for Phosphorylation , 1998, The Journal of experimental medicine.

[20]  C. Turck,et al.  BLNK: a central linker protein in B cell activation. , 1998, Immunity.

[21]  C. Greider.  Telomerase activity, cell proliferation, and cancer. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Kallassy,et al.  Growth arrest of immortalized human keratinocytes and suppression of telomerase activity by p21WAF1 gene expression , 1998, Molecular carcinogenesis.

[23]  L. Yoo,et al.  B-cell lines immortalized with an Epstein-Barr virus mutant lacking the Cp EBNA2 enhancer are biased toward utilization of the oriP-proximal EBNA gene promoter Wp1 , 1997, Journal of virology.

[24]  R. Longnecker,et al.  The immunoreceptor tyrosine-based activation motif of Epstein-Barr virus LMP2A is essential for blocking BCR-mediated signal transduction. , 1997, Virology.

[25]  G. Roos,et al.  Telomeres and telomerase in normal and malignant haematopoietic cells. , 1997, European journal of cancer.

[26]  J. Banchereau,et al.  Epstein‐Barr virus latent membrane protein (LMP1) is not sufficient to maintain proliferation of B cells but both it and activated CD40 can prolong their survival. , 1996, The EMBO journal.

[27]  D. Thorley-Lawson,et al.  Detection of the latent form of Epstein-Barr virus DNA in the peripheral blood of healthy individuals , 1996, Journal of virology.

[28]  J. McDougall,et al.  Telomerase activation by the E6 gene product of human papillomavirus type 16 , 1996, Nature.

[29]  J. Schlessinger,et al.  Signal transduction by the α6β4 integrin: distinct β4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes , 1995 .

[30]  G. Winberg,et al.  A subpopulation of normal B cells latently infected with Epstein-Barr virus resembles Burkitt lymphoma cells in expressing EBNA-1 but not EBNA-2 or LMP1 , 1995, Journal of virology.

[31]  C. Ware,et al.  The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family , 1995, Cell.

[32]  E. Kieff,et al.  Integral membrane protein 2 of Epstein-Barr virus regulates reactivation from latency through dominant negative effects on protein-tyrosine kinases. , 1995, Immunity.

[33]  W. Hammerschmidt,et al.  Immortalization of human B lymphocytes by a plasmid containing 71 kilobase pairs of Epstein-Barr virus DNA , 1995, Journal of virology.

[34]  L. Young,et al.  Epstein-Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state , 1994, Journal of virology.

[35]  L. Matsuuchi,et al.  Structure and function of the B-cell antigen receptor. , 1994, Chemical immunology.

[36]  E. Kieff,et al.  An integral membrane protein (LMP2) blocks reactivation of Epstein-Barr virus from latency following surface immunoglobulin crosslinking. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[37]  E. Kieff,et al.  Epstein-Barr virus latent membrane protein 2A blocks calcium mobilization in B lymphocytes , 1993, Journal of virology.

[38]  E. Kieff,et al.  An Epstein-Barr virus transformation-associated membrane protein interacts with src family tyrosine kinases , 1992, Journal of virology.

[39]  D. Rowe,et al.  Epstein-Barr virus latent gene expression in uncultured peripheral blood lymphocytes , 1992, Journal of virology.

[40]  U. Nater,et al.  Epstein-Barr virus. , 1991, The Journal of family practice.

[41]  Miller Ad,et al.  Improved Retroviral Vectors for Gene Transfer and Expression , 1989 .

[42]  M. Perricaudet,et al.  A spliced Epstein‐Barr virus gene expressed in immortalized lymphocytes is created by circularization of the linear viral genome. , 1988, The EMBO journal.

[43]  L. Young,et al.  Differences in B cell growth phenotype reflect novel patterns of Epstein‐Barr virus latent gene expression in Burkitt's lymphoma cells. , 1987, The EMBO journal.

[44]  K. Pflüger,et al.  Karyotype and ultrastructure of a colony stimulating factor (CSF) producing cell line (5637) originated from a carcinoma of the human urinary bladder , 1986, Blut.

[45]  J. M. Yoffey,et al.  Establishment in continuous culture of a new type of lymphocyte from a “burkitt‐like” malignant lymphoma (line d.g.‐75) , 1977, International journal of cancer.

[46]  T. B. Miller,et al.  Genetic characteristics of the HeLa cell. , 1976, Science.

[47]  S. Aaronson,et al.  In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors. , 1973, Journal of the National Cancer Institute.

[48]  W. Robinson.  Human tumor viruses , 1973, California medicine.

[49]  Pelayo Vilar,et al.  Nasopharyngeal Carcinoma , 1966 .

[50]  R. Longnecker,et al.  Epstein-Barr virus latency: LMP2, a regulator or means for Epstein-Barr virus persistence? , 2000, Advances in cancer research.

[51]  R. DePinho,et al.  Cellular senescence: mitotic clock or culture shock? , 2000, Cell.

[52]  Y. Cong,et al.  The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. , 1999, Human molecular genetics.

[53]  Andrew C. Chan,et al.  BLNK Required for Coupling Syk to PLCγ2 and Rac1-JNK in B Cells , 1999 .

[54]  T. Kurosaki,et al.  BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells. , 1999, Immunity.

[55]  M. Sudol,et al.  Structure and function of the WW domain. , 1996, Progress in biophysics and molecular biology.

[56]  E. Kieff,et al.  Epstein-Barr virus protein LMP2A regulates reactivation from latency by negatively regulating tyrosine kinases involved in sIg-mediated signal transduction. , 1994, Infectious agents and disease.

[57]  J. Cambier,et al.  Signal transduction by the B cell antigen receptor and its coreceptors. , 1994, Annual review of immunology.

[58]  H. zur Hausen.  Viruses in human cancers. , 1991, Science.

[59]  A. Miller,et al.  Improved retroviral vectors for gene transfer and expression. , 1989, BioTechniques.

[60]  T. Ooka.  The molecular biology of Epstein-Barr virus. , 1985, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.