The oncogenic membrane protein LMP1 sequesters TRAF3 in B-cell lymphoma cells to produce functional TRAF3 deficiency

Bangalore-Prakash, Pradeep; Stunz, Laura L.; Mambetsariev, Nurbek; Whillock, Amy L.; Hostager, Bruce S.; Bishop, Gail A.

doi:10.1182/bloodadvances.2017009670

Cited by 12 publications

(14 citation statements)

References 85 publications

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“…The cellular signaling pathways targeted by LMP-1 share functional characteristics with members of the tumor necrosis factor (TNF) receptor superfamily. Molecular studies have revealed that the C-terminal domains (CTAR1 and CTAR2) of LMP-1 play an important role in signal transduction through mimicking the CD40-mediated signaling ( 50 ). The LMP-1 protein binds the tumor necrosis factor receptor-associated factor (TRAF) proteins and the TNF receptor-associated death domain protein (TRADD) activating several intracellular pathways including NF-κB, the mitogen-activated protein kinases JNK and p38, the small GTPase Cdc42, and the JAK/AP-1/STAT cascades.…”

Section: The Lmp-1 Oncogene Variationmentioning

confidence: 99%

“…The LMP-1 protein binds the tumor necrosis factor receptor-associated factor (TRAF) proteins and the TNF receptor-associated death domain protein (TRADD) activating several intracellular pathways including NF-κB, the mitogen-activated protein kinases JNK and p38, the small GTPase Cdc42, and the JAK/AP-1/STAT cascades. Activation of these intracellular signaling cascades enhances cell survival and proliferation and may account for many of the cellular changes observed in response to LMP-1 ( 50 – 52 ). Moreover, the LPM1 protein works as homologous to the TNF-receptor family in the B lymphocytes and epithelial cells ( 6 ).…”

Section: The Lmp-1 Oncogene Variationmentioning

confidence: 99%

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Epstein–Barr Virus Epidemiology, Serology, and Genetic Variability of LMP-1 Oncogene Among Healthy Population: An Update

et al. 2018

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The Epstein–Barr virus (EBV) is a DNA lymphotropic herpesvirus and the causative agent of infectious mononucleosis. EBV is highly prevalent since it affects more than 90% of individuals worldwide and has been linked to several malignancies including PTLDs, which are one of the most common malignancies following transplantation. Among all the EBV genes, most of the recent investigations focused on studying the LMP-1 oncogene because of its high degree of polymorphism and association with tumorigenic activity. There are two main EBV genotypes, Type 1 and 2, distinguished by the differences in the EBNA-2 gene. Further sub genotyping can be characterized by analyzing the LMP-1 gene variation. The virus primarily transmits through oral secretions and persists as a latent infection in human B-cells. However, it can be transmitted through organ transplantations and blood transfusions. In addition, symptoms of EBV infection are not distinguishable from other viral infections, and therefore, it remains questionable whether there is a need to screen for EBV prior to blood transfusion. Although the process of leukoreduction decreases the viral copies present in the leukocytes, it does not eliminate the risk of EBV transmission through blood products. Here, we provide a review of the EBV epidemiology and the genetic variability of the oncogene LMP-1. Then, we underscore the findings of recent EBV seroprevalence and viremia studies among blood donors as a highly prevalent transfusion transmissible oncovirus.

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Section: The Lmp-1 Oncogene Variationmentioning

confidence: 99%

Section: The Lmp-1 Oncogene Variationmentioning

confidence: 99%

Epstein–Barr Virus Epidemiology, Serology, and Genetic Variability of LMP-1 Oncogene Among Healthy Population: An Update

et al. 2018

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“…Mechanistically, TRAF3 inhibits the IL-6-IL-6R-JAK1-STAT3 survival and differentiation pathway in plasma cells by facilitating the association of PTPN22 with JAK1 ( 171 ). Furthermore, the EBV-encoded oncoprotein LMP1 sequesters TRAF3 to produce functional TRAF3 deficiency in human and mouse B lymphoma cells ( 172 , 173 ). Intriguingly, lymphocyte-specific TRAF3 transgenic mice also develop plasmacytosis, autoimmunity, inflammation, and cancers, which are likely caused by hyper-responsiveness of B cells to antigens and TLR agonists ( 55 ).…”

Section: Traf3mentioning

confidence: 99%

Genetic Alterations of TRAF Proteins in Human Cancers

et al. 2018

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The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors. TRAF-dependent signaling pathways participate in a diverse array of important cellular processes, including the survival, proliferation, differentiation, and activation of different cell types. Many of these TRAF-dependent signaling pathways have been implicated in cancer pathogenesis. Here we analyze the current evidence of genetic alterations of TRAF molecules available from The Cancer Genome Atlas (TCGA) and the Catalog of Somatic Mutations in Cancer (COSMIC) as well as the published literature, including copy number variations and mutation landscape of TRAFs in various human cancers. Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers. These include pancreatic cancer, meningioma, breast cancer, prostate cancer, lung cancer, liver cancer, head and neck cancer, stomach cancer, colon cancer, bladder cancer, uterine cancer, melanoma, sarcoma, and B cell malignancies, among others. Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs. Taken together, the information presented in this review provides a rationale for the development of therapeutic strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in different human cancers by precision medicine.

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“…While TRAF3 genetic loss is associated with B cell malignancies, this is not the only mechanism by which a B cell can become TRAF3 protein-deficient, with the tumor-predisposing consequences discussed above. Our laboratory recently reported the results of TRAF3 protein staining of several 100 human DLBCL samples, which revealed that more than 30% of these BCL had low to undetectable TRAF3 protein expression ( 114 ). It was previously demonstrated that the EBV transforming protein LMP1 binds TRAF3 with considerably enhanced affinity, compared to the normal cellular receptor that it mimics, CD40 ( 21 , 23 ).…”

Section: Traf3 and B Cell Malignanciesmentioning

confidence: 99%

“…It was previously demonstrated that the EBV transforming protein LMP1 binds TRAF3 with considerably enhanced affinity, compared to the normal cellular receptor that it mimics, CD40 ( 21 , 23 ). Thus, we examined whether B cell expression of LMP1 is associated with sequestration of TRAF3 in the plasma membrane, resulting in decreased availability of TRAF3 to downregulate various pro-survival signaling pathways discussed above; this was found to be the case ( 114 ). It is also well-documented that signaling to B cells via CD40 or BAFFR leads to poly-ubiquitination and degradation of TRAF3 [reviewed in ( 33 )].…”

Section: Traf3 and B Cell Malignanciesmentioning

confidence: 99%

TRAF3 as a Multifaceted Regulator of B Lymphocyte Survival and Activation

2018

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The adaptor protein TNF receptor-associated factor 3 (TRAF3) serves as a powerful negative regulator in multiple aspects of B cell biology. Early in vitro studies in transformed cell lines suggested the potential of TRAF3 to inhibit signaling by its first identified binding receptor, CD40. However, because the canonical TRAF3 binding site on many receptors also mediates binding of other TRAFs, and whole-mouse TRAF3 deficiency is neonatally lethal, an accurate understanding of TRAF3's specific functions was delayed until conditional TRAF3-deficient mice were produced. Studies of B cell-specific TRAF3-deficient mice, complemented by investigations in normal and malignant mouse and human B cells, reveal that TRAF3 has powerful regulatory roles that are unique to this TRAF, as well as functions context-specific to the B cell. This review summarizes the current state of knowledge of these roles and functions. These include inhibition of signaling by plasma membrane receptors, negative regulation of intracellular receptors, and restraint of cytoplasmic NF- κB pathways. TRAF3 is also now known to function as a resident nuclear protein, and to impact B cell metabolism. Through these and additional mechanisms TRAF3 exerts powerful restraint upon B cell survival and activation. It is thus perhaps not surprising that TRAF3 has been revealed as an important tumor suppressor in B cells. The many and varied functions of TRAF3 in B cells, and new directions to pursue in future studies, are summarized and discussed here.

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The oncogenic membrane protein LMP1 sequesters TRAF3 in B-cell lymphoma cells to produce functional TRAF3 deficiency

Cited by 12 publications

References 85 publications

Epstein–Barr Virus Epidemiology, Serology, and Genetic Variability of LMP-1 Oncogene Among Healthy Population: An Update

Epstein–Barr Virus Epidemiology, Serology, and Genetic Variability of LMP-1 Oncogene Among Healthy Population: An Update

Genetic Alterations of TRAF Proteins in Human Cancers

TRAF3 as a Multifaceted Regulator of B Lymphocyte Survival and Activation

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