Epstein-Barr virus oncoprotein LMP1 mediates survivin upregulation by p53 contributing to G1/S cell cycle progression in nasopharyngeal carcinoma

Abstract

Latent membrane protein 1 (LMP1) is an important oncogenic protein encoded by Epstein-Barr virus (EBV) and plays an important role in the development of nasopharyngeal carcinoma (NPC). Our previous study has shown that p53 protein was accumulated and phosphorylated in NPC, implying its transcription factor activity in NPC tumorigenesis. However, the biological function and potential downstream target of p53 mediated by LMP1 in NPC remain unknown. In this study, we found that LMP1 simultaneously induced upregulation of both p53 and survivin at the protein level, as well as their phosphorylation. Knockdown of p53 by siRNA revealed that LMP1 increased survivin expression by p53 directly. Furthermore, we found that LMP1 upregulated survivin by p53 at the transcriptional level by increasing p53-mediated survivin promoter activity and DNA binding activity. Moreover, LMP1 induced the co-localization of p53 and survivin in the nucleus, conferring to their related functions in NPC tumorigenesis. We further found that p53 promoted G1/S cell cycle progression, but did not induce apoptosis in LMP1-positive NPC cells. Collectively, these findings suggest that p53 acting as a transcription factor promotes the transcriptional activity of survivin, and further increases its protein expression and phosphorylation in the regulation of LMP1, thus, leading to G1/S cell cycle progression with no effect on apoptosis in NPC tumorigenesis.

Autocrine CCL3 and CCL4 Induced by the Oncoprotein LMP1 Promote Epstein-Barr Virus-Triggered B Cell Proliferation

“…(ii) The synthesis and secretion of IL-1, IL-6, IL-8, and IL-10 can be enhanced by LMP1, and these then act in an autocrine manner to promote cell proliferation and affect the host immune response (27-29). (iii) LMP1 can stimulate the antiapoptotic genes A20, BCL-2, and survivin to prevent infected cells from apoptosis (30)(31)(32). (iv) LMP1 can facilitate the degradation of p53 by augmenting the expression of mouse double minute 2 (MDM2) and mitogen-activated protein kinase (33,34).…”

Interference of Fisetin with Targets of the Nuclear Factor-κB Signal Transduction Pathway Activated by Epstein-Barr Virus Encoded Latent Membrane Protein 1

“…In human epithelial cells, LMP1 alters many functional properties that are involved in tumor progression and invasions (Kim et al, 2000;Adham et al, 2012;Bambang et al, 2010). Activation of different signal transduction pathways mediates various downstream pathological effects of LMP1 expression, including cell proliferation, anti-apoptosis and metastasis (Eliopoulos et al, 2001;Guo et al, 2012).…”

“…NF-κB participates in the induction of cellular genes encoding apoptosis molecules (Xu et al, 2012;Yang et al, 2012 (Vermeulen et al, 2003).…”

Epstein-Barr Virus and Classical Hodgkin’s Lymphoma

“…9 и 10) [21,32,33]. Показано также, что LMP1 подавляет (как правило, опосредованно) экспрессию ряда ключевых опу-холевых супрессоров (р53, RASSF1A), нарушает работу проверочных точек клеточного цикла G1-S, обеспечивая выживание поврежденных клеток [34,35]. LMP1 ин-дуцирует экспрессию провоспалительных цитокинов, наделяет инфицированные клетки резистентностью к апоптозу, вызывает эпителиально-мезенхимальный переход, усиливает подвижность клеток, их инвазию и ме-тастазирование, селективно подавляет либо активирует экспрессию ряда клеточных микроРНК и т. д.…”