EBV Infection of Human B Lymphocytes Leads to Down-Regulation of Bim Expression: Relationship to Resistance to Apoptosis

Clybouw, Cyril; Mchichi, Bouchra El; Mouhamad, Shahul; Auffredou, Marie Thérèse; Bourgeade, Marie‐Françoise; Sharma, Surendra; Leca, Gérald; Vázquez, Aimé

doi:10.4049/jimmunol.175.5.2968

Cited by 51 publications

(46 citation statements)

References 33 publications

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“…Phosphorylation of BIM by ERK was reported to be critical for the antiapoptotic activity of this kinase. [56][57][58][59][60] However, a recent study has shown that ERK-mediated direct phosphorylation of BIM does not have a major role in the control of the proapoptotic activity of this BH3-only protein within the whole animal. 61 Both BIM and BMF were shown to be sequestered by binding to elements of the cytoskeleton, thereby restraining their pro-apoptotic activity.…”

Section: The Bcl-2-regulated Apoptotic Pathwaymentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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Section: The Bcl-2-regulated Apoptotic Pathwaymentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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“…Bim is also particularly important in the regulation of apoptosis during B-cell development, and its regulation by cMyc can play an important role in the pathogenesis of BL (8,11,26). Furthermore, a recent report indicated that EBV-converted BL41 and Ramos cells express lower levels of Bim than the parental lines (7). Protein extracts from the matched pairs of EBVϪve and EBVϩve cells previously screened for caspase activity were analyzed by Western blotting and probed for expression of the Bim proteins (Fig.…”

Section: Vol 81 2007 Ebv-induced Resistance To Microtubule-disruptimentioning

confidence: 99%

Epstein-Barr Virus-Induced Resistance to Drugs That Activate the Mitotic Spindle Assembly Checkpoint in Burkitt's Lymphoma Cells

Leão

Anderton

Wade

et al. 2007

J Virol

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Epstein-Barr virus (EBV)is associated with a number of human cancers, and latent EBV gene expression has been reported to interfere with cell cycle checkpoints and cell death pathways. Here we show that latent EBV can compromise the mitotic spindle assembly checkpoint and rescue Burkitt's lymphoma (BL)-derived cells from caspase-dependent cell death initiated in aberrant mitosis. This leads to unscheduled mitotic progression, resulting in polyploidy and multi-and/or micronucleation. The EBV latent genes responsible for this phenotype are expressed from the P3HR1 strain of virus and several viruses with similar genomic deletions that remove the EBNA2 gene. Although EBNA2 and the latent membrane proteins are not expressed, the EBNA3 proteins are present in these BL cells. Survival of the EBV-positive cells is not consistently associated with EBV lytic gene expression or with the genes that are expressed in EBV latency I BL cells (i.e., EBNA1, EBERs, and BARTs) but correlates with reduced expression of the cellular proapoptotic BH3-only protein Bim. These data suggest that a subset of latent EBV gene products may increase the likelihood of damaged DNA being inherited because of the impaired checkpoint and enhanced survival capacity. This could lead to greater genetic diversity in progeny cells and contribute to tumorigenesis. Furthermore, since it appears that this restricted latent EBV expression interferes with the responses of Burkitt's lymphoma-derived cells to cytotoxic drugs, the results of this study may have important therapeutic implications in the treatment of some BL. Epstein-Barr virus (EBV) is a gammaherpesvirus that pro-duces an asymptomatic infection in the majority of the human population. However, EBV is also associated with a number of human tumors of B-cell, T-cell, and epithelial origin. These include Burkitt's lymphoma (BL), some types of Hodgkin's lymphoma, immunoblastic B lymphoma in the immunosuppressed, nasopharyngeal carcinoma, and gastric carcinoma. Although the precise contribution EBV makes to the development of these diseases is not yet known, it has been suggested that interference with cell cycle checkpoints and cell death pathways by EBV may play an important role in B lymphomagenesis (reviewed in reference 20).In vitro, EBV has the ability to infect and transform primary B cells into continuously proliferating lymphoblastoid cell lines (LCLs) that have a pattern of viral gene expression known as latency III. This is characterized by the expression of nine viral proteins: six Epstein-Barr nuclear antigens (EBNAs) (EBNA1, -2, -3A, -3B, -3C, and -LP) and three latent membrane proteins (LMPs) (LMP1, -2A, and -2B). Additional RNA species (the EBV-encoded RNAs [EBERs] and the BamHIA rightward transcripts [BARTs]) are also expressed during latency III, but their significance is not fully understood (3). It has been reported from studies with recombinant EBV that only six of the latency III proteins (EBNA1, -2, -3A, -3C, -LP, and -LMP1) are essential for efficient transformation of B cells...

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“…16 To test the biological function of SPRY2 W119 variant, we investigated the MAPK/ERK pathway by western blot in the available cell lines. Because in EBV-transformed B lymphoblasts the ERK1/2 pathway is constitutively active, 17 the level of phosphoERK1/2 (pERK1/2) was directly analyzed. pERK1/2 was hypophosphorylated in all mutation carriers as well as in the LCL156 and LCL157, compared with the control cell lines and to IV-46, negative for SPRY2 mutations (Figures 3a and b).…”

Section: Exome Sequencing and Bioinformatics Analysismentioning

confidence: 99%

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

Milillo¹,

Carpia²,

Costanzi

et al. 2015

Eur J Hum Genet

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IgA nephropathy (IgAN) represents the most common primary glomerulonephritis worldwide with a prevalence of 25-50% among patients with primary glomerulopathies. In~5-10% of the patients the disease segregates with an autosomal dominant (AD) pattern. Association studies identified loci on chromosomes 1q32, 6p21, 8p23, 17p13, 22q12, whereas classical linkage studies on AD families identified loci on chromosomes 2q36, 4q26-31, 6q22, 17q12-22. We have studied a large Sicilian family where IgAN segregates with an AD transmission. To identify the causal gene, the exomes of two affected and one unaffected individual have been sequenced. From the bioinformatics analysis a p.(Arg119Trp) variant in the SPRY2 gene was identified as the probable disease-causing mutation. Moreover, functional characterization of this variant showed that it is responsible for the inhibition of the MAPK/ERK1/2 pathway. The same effect was observed in two sporadic IgAN patients carriers of wild-type SPRY2, suggesting that downregulation of the MAPK/ERK1/2 pathway represents a common mechanism leading to IgAN.

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EBV Infection of Human B Lymphocytes Leads to Down-Regulation of Bim Expression: Relationship to Resistance to Apoptosis

Cited by 51 publications

References 33 publications

The BCL-2 protein family, BH3-mimetics and cancer therapy

The BCL-2 protein family, BH3-mimetics and cancer therapy

Epstein-Barr Virus-Induced Resistance to Drugs That Activate the Mitotic Spindle Assembly Checkpoint in Burkitt's Lymphoma Cells

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

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