Cross talk between EBV and telomerase: The role of TERT and NOTCH2 in the switch of latent/lytic cycle of the virus

S. Giunco, A. Celeghin, K. Gianesin, R. Dolcetti, S. Indraccolo, A. De Rossi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Epstein-Barr virus (EBV)-associated malignancies, as well as lymphoblastoid cell lines (LCLs), obtained in vitro by EBV infection of B cells, express latent viral proteins and maintain their ability to grow indefinitely through inappropriate activation of telomerespecific reverse transcriptase (TERT), the catalytic component of telomerase. Our previous studies demonstrated that high levels of TERT expression in LCLs prevent the activation of EBV lytic cycle, which is instead triggered by TERT silencing. As lytic infection promotes the death of EBV-positive tumor cells, understanding the mechanism(s) by which TERT affects the latent/lytic status of EBV may be important for setting new therapeutic strategies. BATF, a transcription factor activated by NOTCH2, the major NOTCH family member in B cells, negatively affects the expression of BZLF1, the master regulator of viral lytic cycle. We therefore analyzed the interplay between TERT, NOTCH and BATF in LCLs and found that high levels of endogenous TERT are associated with high NOTCH2 and BATF expression levels. In addition, ectopic expression of TERT in LCLs with low levels of endogenous telomerase was associated with upregulation of NOTCH2 and BATF at both mRNA and protein levels. By contrast, infection of LCLs with retroviral vectors expressing functional NOTCH2 did not alter TERT transcript levels. Luciferase reporter assays, demonstrated that TERT significantly activated NOTCH2 promoter in a dose-dependent manner.We also found that NF-κB pathway is involved in TERT-induced NOTCH2 activation. Lastly, pharmacologic inhibition of NOTCH signaling triggers the EBV lytic cycle, leading to the death of EBV-infected cells. Overall, these results indicate that TERT contributes to preserve EBV latency in B cells mainly through the NOTCH2/BAFT pathway, and suggest that NOTCH2 inhibition may represent an appealing therapeutic strategy against EBV-associated malignancies.

Original languageEnglish
Article numbere1774
JournalCell Death and Disease
Volume6
Issue number5
DOIs
Publication statusPublished - May 1 2015

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Telomerase
RNA-Directed DNA Polymerase
Human Herpesvirus 4
Viruses
Cell Line
B-Lymphocytes
Virus Latency
Neoplasms
Epstein-Barr Virus Infections
Aptitude
Viral Proteins
Infection
Luciferases
Transcription Factors
Up-Regulation

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Cross talk between EBV and telomerase : The role of TERT and NOTCH2 in the switch of latent/lytic cycle of the virus. / Giunco, S.; Celeghin, A.; Gianesin, K.; Dolcetti, R.; Indraccolo, S.; De Rossi, A.

In: Cell Death and Disease, Vol. 6, No. 5, e1774, 01.05.2015.

Research output: Contribution to journalArticle

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