Epstein-Barr virus LMP2A bypasses p53 inactivation in a MYC model of lymphomagenesis

Bieging, Kathryn T.; Amick, Alexandra C.; Longnecker, Richard

doi:10.1073/pnas.0907994106

Cited by 37 publications

(70 citation statements)

References 35 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LMP1 decreases expression of both ATM and p53 (35,44). Furthermore, both LMP1 and LMP2A inhibit p53-mediated apoptosis (7,30,75). LMP1 and LMP2A have both been reported to inhibit lytic viral reactivation in vitro (3,67,68,74), and we recently reported that LMP1-and LMP2A-expressing B cells do not express early lytic viral proteins in EBV-infected humanized mice, even when mice are infected with a "superlytic" EBV mutant that results in high-level Z/BMRF1 expression (59).…”

Section: Discussionmentioning

confidence: 97%

The Cellular Ataxia Telangiectasia-Mutated Kinase Promotes Epstein-Barr Virus Lytic Reactivation in Response to Multiple Different Types of Lytic Reactivation-Inducing Stimuli

Hagemeier

Barlow

Qiao

et al. 2012

J Virol

View full text Add to dashboard Cite

The Epstein-Barr virus (EBV) latent-to-lytic switch is mediated by the viral proteins BZLF1 (Z), BRLF1 (R), and BRRF1 (Na). Since we previously showed that DNA-damaging agents (including chemotherapy and irradiation) can induce EBV lytic reactivation and recently demonstrated that wild-type p53 contributes to lytic reactivation, we investigated the role of the ATM kinase during EBV reactivation. ATM phosphorylates and activates p53, as well as numerous other substrates involved in the cellular DNA damage response. Using an ATM inhibitor (KU55933), we found that ATM activity is required for efficient induction of EBV lytic gene expression by a variety of different stimuli, including a histone deacetylase (HDAC) inhibitor, the transforming growth factor ␤ (TGF-␤) cytokine, a demethylating agent (5-azacytidine), B cell receptor engagement with anti-IgG antibody, hydrogen peroxide, and the proteosome inhibitor bortezomib. In EBV-infected AGS (gastric) cells, knockdown of ATM, or p53, expression inhibits EBV reactivation. Conversely, treatment of these cells with nutlin-3 (which activates p53 and ATM) robustly induces lytic reactivation in a p53-and ATM-dependent manner. The ability of the EBV R and Na proteins to induce lytic reactivation in EBV-infected AGS cells is ATM dependent. However, overexpression of Z induces lytic gene expression in the presence or absence of ATM activity. Our results suggest that ATM enhances Z promoter activity in the context of the intact EBV genome and that p53 contributes to the ATM effect. Nevertheless, since we found that ATM inhibitors also reduce lytic reactivation in Burkitt lymphoma cells that have no p53, additional ATM substrates must also contribute to the ATM effect. E pstein-Barr virus (EBV) is a gammaherpesvirus that is the cause of infectious mononucleosis and is associated with a variety of epithelial and B cell cancers, including nasopharyngeal carcinoma (NPC), a subset of gastric carcinomas, Burkitt lymphoma (BL), and Hodgkin's disease (77,102). Like all herpesviruses, EBV can infect cells in either latent or lytic forms. Following infection of humans, EBV establishes long-term viral latency in the memory B cell compartment but can be reactivated to undergo the lytic form of infection following plasma cell differentiation (51). EBV infection of normal epithelial cells generally results in lytic infection (32,93,94), although EBV ϩ epithelial cell tumors such as NPCs and gastric carcinomas are primarily composed of cells with latent forms of infection (48,77). Both the latent and lytic forms of EBV infection are essential for the long-term success of the virus, and the latent-lytic switch is tightly controlled by both cellular and viral factors.The two EBV immediate-early (IE) proteins, BZLF1 (Z, also known as Zta, ZEBRA, or EB1) and BRLF1 (R), are transcription factors that activate expression of lytic viral promoters, and overexpression of either the Z or R IE protein is sufficient to reactivate the lytic form of EBV infection in many latently infected cell lines (2, ...

show abstract

Section: Discussionmentioning

confidence: 97%

The Cellular Ataxia Telangiectasia-Mutated Kinase Promotes Epstein-Barr Virus Lytic Reactivation in Response to Multiple Different Types of Lytic Reactivation-Inducing Stimuli

Hagemeier

Barlow

Qiao

et al. 2012

J Virol

View full text Add to dashboard Cite

show abstract

“…[17][18][19] These mice develop a fatal lymphoma within several months. We developed a transgenic mouse model to study the role of LMP2A in BL 20,21 by crossing -MYC transgenic mice 18 with mice that express LMP2A in B cells. 22,23 LMP2A/-MYC mice also develop tumors, and tumor onset is accelerated compared with -MYC mice The online version of this article contains a data supplement.…”

Section: Introductionmentioning

confidence: 99%

“…20,21 Alteration of the major tumor suppressor p53 is common in tumors from MYC transgenic mice. 19 However, the p53 pathway was functionally intact in LMP2A/-MYC tumor cells.…”

Section: Introductionmentioning

confidence: 99%

“…19 However, the p53 pathway was functionally intact in LMP2A/-MYC tumor cells. 20 To investigate the functions of LMP2A in the context of deregulated MYC and understand mechanism of acceleration of tumor onset and p53 bypass by LMP2A in our mouse model of BL, we analyzed total gene expression in both tumor and pretumor B cells from -MYC and LMP2A/-MYC mice. In comparing expression profiles between pretumor B cells from -MYC and LMP2A/-MYC mice, a large number of genes were significantly differentially expressed.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A shared gene expression signature in mouse models of EBV-associated and non–EBV-associated Burkitt lymphoma

Bieging

Fish

Bondada

et al. 2011

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, LMP2A probably maintains cell survival by modulating Bcl-xL levels and Bcl-2 expression patterns in the absence of B cell receptor signaling (Portis and Longnecker, 2004). Other studies have shown that LMP2A can bypass the intact p53 pathway in the c-MYC model of lymphomagenesis (Bieging et al, 2009;. Interestingly, the regulation was selective for Bcl-2, since the NF-κB inhibitor apparently affects the levels of Bcl-2 only in LMP2A/HEL-Tg B cells, not in the Bcl-2-positive HEL-Tg B cell .…”

Section: Bcl-2mentioning

confidence: 99%

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

Mao

2013

J. Zhejiang Univ. Sci. B

View full text Add to dashboard Cite

Epstein-Barr virus (EBV), a human gammaherpesvirus carried by more than 90% of the world's population, is associated with malignant tumors such as Burkitt's lymphoma (BL), Hodgkin lymphoma, post-transplant lymphoma, extra-nodal natural killer/T cell lymphoma, and nasopharyngeal and gastric carcinomas in immune-compromised patients. In the process of infection, EBV faces challenges: the host cell environment is harsh, and the survival and apoptosis of host cells are precisely regulated. Only when host cells receive sufficient survival signals may they immortalize. To establish efficiently a lytic or long-term latent infection, EBV must escape the host cell immunologic mechanism and resist host cell apoptosis by interfering with multiple signaling pathways. This review details the apoptotic pathway disrupted by EBV in EBV-infected cells and describes the interactions of EBV gene products with host cellular factors as well as the function of these factors, which decide the fate of the host cell. The relationships between other EBV-encoded genes and proteins of the B-cell leukemia/lymphoma (Bcl) family are unknown. Still, EBV seems to contribute to establishing its own latency and the formation of tumors by modifying events that impact cell survival and proliferation as well as the immune response of the infected host. We discuss potential therapeutic drugs to provide a foundation for further studies of tumor pathogenesis aimed at exploiting novel therapeutic strategies for EBV-associated diseases.

show abstract

Epstein-Barr virus LMP2A bypasses p53 inactivation in a MYC model of lymphomagenesis

Cited by 37 publications

References 35 publications

The Cellular Ataxia Telangiectasia-Mutated Kinase Promotes Epstein-Barr Virus Lytic Reactivation in Response to Multiple Different Types of Lytic Reactivation-Inducing Stimuli

The Cellular Ataxia Telangiectasia-Mutated Kinase Promotes Epstein-Barr Virus Lytic Reactivation in Response to Multiple Different Types of Lytic Reactivation-Inducing Stimuli

A shared gene expression signature in mouse models of EBV-associated and non–EBV-associated Burkitt lymphoma

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

Contact Info

Product

Resources

About