Epstein-Barr virus nuclear antigen 2 retards cell growth, induces p21WAF1 expression, and modulates p53 activity post-translationally

Lin, Chang-Shen; Kuo, H.P.; Chen, Jen‐Yang; Yang, Czau‐Siung; Wang, Won‐Bo

doi:10.1006/jmbi.2000.4121

Cited by 29 publications

(18 citation statements)

References 57 publications

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“…For example, as mentioned above, there are multiple miRNAs directly regulated p21 in the literature. Notably, various factors, such as the EBV nuclear antigen 2 and lactotransferrin, have been reported to regulate p21 in NPC (Lin et al, 2000;Zhou et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

MiR-663, a microRNA targeting p21WAF1/CIP1, promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma

et al. 2012

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Section: Discussionmentioning

confidence: 99%

MiR-663, a microRNA targeting p21WAF1/CIP1, promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma

et al. 2012

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“…The EBNA2 viral protein has been shown to induce p21 WAF1 production in various types of cell. 48 It, therefore, could be hypothesized that EBNA2 is involved in the resistance of latency III BL cells to drugs. However, other studies have shown that lymphoblastoid cell lines (LCLs) and EBV-infected primary B cells, both of which have a latency III phenotype (and therefore produce EBNA2), undergo apoptosis in response to various DNA-damaging agents.…”

Section: Discussionmentioning

confidence: 99%

Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein–Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells

et al. 2009

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p53 inactivation is often observed in Burkitt's lymphoma (BL) cells, because of either mutations in p53 gene or an overexpression of the p53-negative regulator MDM2. Epstein-Barr virus (EBV) is present in virtually 100% of BL cases occurring in endemic areas, but in only 10-20% of sporadic cases. In EBV(À) BL cells, reactivation of p53, induced by reducing MDM2 protein level, led to apoptosis. We show here that nutlin-3, a potent antagonist of MDM2, activates the p53 pathway in all BL cell lines harboring wild-type p53, regardless of EBV status. However, nutlin-3 strongly induced apoptosis in EBV(À) or latency I EBV( þ ) cells, whereas latency III EBV( þ ) cells were much more resistant. Prior treatment with sublethal doses of nutlin-3 sensitizes EBV(À) or latency I EBV( þ ) cells to apoptosis induced by etoposide or melphalan, but protects latency III EBV( þ ) cells. p21 WAF1 which is overexpressed in the latter, is involved in this protective effect, as siRNA-mediated inhibition of p21 WAF1 restores sensitivity to etoposide. Nutlin-3 protects latency III BL cells by inducing a p21 WAF1 -mediated G1 arrest. Most BL patients with wild-type p53 tumors could therefore benefit from treatment with nutlin-3, after a careful determination of the latency pattern of EBV in infected patients.

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“…The mechanism of EBVinduced p53 overexpression is further complicated by other EBV gene products such as BZLF1 and EBNA5, which can also bind p53 (28,29). In addition, EBNA2 can also promote p53 phosphorylation and induce p21 expression (30). Hence, it is likely that multiple EBV players interact with p53, ultimately resulting in its nuclear accumulation, and probable compromised function.…”

Section: Fig 3 Kaplan-meier Plots For Os (A) and Dfs (B) As A Functmentioning

confidence: 99%

Prognostic Significance of the Epstein-Barr Virus, p53, Bcl-2, and Survivin in Nasopharyngeal Cancer

Yip

Shi

Pintilie

et al. 2006

Clinical Cancer Research

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Purpose: Nasopharyngeal cancer (NPC) is a malignant epithelial carcinoma which is intimately associated with EBV. The latent presence of EBV affects the function of p53, Bcl-2, and survivin. We thus investigated the relationship between EBV status, p53, Bcl-2, and survivin in biopsy specimens from patients with primary NPC. Experimental Design: Archival formalin-fixed, paraffin-embedded NPC biopsies were evaluated in 80 patients treated with curative radiation from a single institution. The presence of EBV was determined using EBER in situ hybridization, whereas p53, Bcl-2, and survivin were assessed using immunohistochemistry. Results: The majority of NPC specimens in this patient cohort were EBER-positive (64 of 78, or 82%), which in turn, was significantly associated with ethnicity (P = 0.0007), and WHO subtype 2A/2B (P = 0.04). EBER-positive tumors were also associated with p53 (P = 0.002), Bcl-2 (P = 0.04), and nuclear survivin (P = 0.03) expression. Patients with EBER-positive NPC fared better, with a 10-year overall survival of 68% versus 48% for EBER-negative patients (P = 0.03). For nuclear survivin, patients with either low or high nuclear survivin fared worse than patients with intermediate survivin expression (P = 0.05), suggesting that there is an optimal proportion of survivin-expressing cells for best function and clinical outcome. Conclusions: With an extended median follow-up time of 11.4 years, EBV status remains a strong predictor for overall survival in NPC. EBV-positive NPC has strong molecular associations with p53, Bcl-2, and survivin expression. Furthermore, we provide clinical data revealing the potentially dual nature of survivin in predicting clinical outcome.Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the head and neck site, with incidences of 20 to 30 per 100,000 people in areas such as Southeast Asia (a region of >100 million people) and the Mediterranean basin (a region of >300 million people) (1). NPC is anatomically located in close proximity to the base of the skull, rendering it a significant challenge for conventional and experimental treatments. In fact, inadequate tumor volume coverage may be partially responsible for the modest 5-year overall survival (OS) rate of f70% when patients are treated with conventional radiotherapy alone (2 -4). Although intensity-modulated radiotherapy does improve local control, the risk of distant metastases remains high at f40% (2). A predilection for developing distant metastases, a young median age of presentation (at f50 years), and the intimate association with EBV are features that render NPC a unique head and neck epithelial malignancy (5).The latent presence of EBV is unique to malignancies such as NPC, Burkitt's lymphoma, Hodgkin's lymphoma, peripheral T cell lymphomas, natural killer cell lymphomas, and gastric carcinomas (1). Approximately 75% to 81% of patients with NPC worldwide harbor the EBV genome, which is present in the type II latency. This form of latency is characterized by the expression ...

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Epstein-Barr virus nuclear antigen 2 retards cell growth, induces p21WAF1 expression, and modulates p53 activity post-translationally

Cited by 29 publications

References 57 publications

MiR-663, a microRNA targeting p21WAF1/CIP1, promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma

MiR-663, a microRNA targeting p21WAF1/CIP1, promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma

Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein–Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells

Prognostic Significance of the Epstein-Barr Virus, p53, Bcl-2, and Survivin in Nasopharyngeal Cancer

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