Activation of the B-cell Surface Receptor CD40 Induces A20, a Novel Zinc Finger Protein That Inhibits Apoptosis

Sarma, Vidya; Lin, Zhiwu; Clark, Lisa B.; Rust, Beth M.; Tewari, Muneesh; Noelle, Randolph J.; Dixit, Vishva M.

doi:10.1074/jbc.270.21.12343

Cited by 185 publications

(105 citation statements)

References 28 publications

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“…DRAK1, a positive mediator of apoptosis, is related to Death-associated Protein Kinase 1 (DAP1). 15 TXBP151 is a novel anti-apoptotic gene that has been shown to mediate the activity of A20, which is induced by CD40/CD40L interaction, 16,17 and its proteolysis is associated with FASmediated apoptosis. IL15 was also overexpressed in the BCL2 translocated cases and it has been implicated in protecting B cells from apoptosis.…”

Section: Discussionmentioning

confidence: 99%

BCL2 Translocation Defines a Unique Tumor Subset within the Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

Iqbal

Sanger

Horsman

et al. 2004

The American Journal of Pathology

267

173

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Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed prognostically important subgroups: germinal center B-cell-like (GCB) DL-BCL, activated B cell-like (ABC) DLBCL, and primary mediastinal large B-cell lymphoma. The t(14;18)(q32; q21) has been reported previously to define a unique subset within the GCB-DLBCL. We evaluated for the translocation in 141 cases of DLBCL that were successfully gene expression profiled. Using a dual-probe fluorescence in situ hybridization assay, we detected the t(14;18) in 17% of DLBCLs and in 34% of the GCB subgroup which contained the vast majority of positive cases. In addition, 12 t(14;18)-positive cases detected by polymerase chain reaction assays on additional samples were added to the fluorescence in situ hybridization-positive cases for subsequent analysis. Immunohistochemical data indicated that BCL2, BCL6, and CD10 protein were preferentially expressed in the t(14;18)-positive cases as compared to t(14;18)-negative cases. Within the GCB subgroup, the expression of BCL2 and CD10, but not BCL6, differed significantly between cases with or without the t(14; 18): 88% versus 24% for BCL2 and 72% versus 32% for CD10, respectively. In the GCB-DLBCL subgroup, a heterogeneous group of genes is overexpressed in the t(14;18)-positive subset, among which BCL2 is a significant discriminator. Interestingly, the t(14;18)-negative subset is dominated by overexpression of cell cycle-associated genes, indicating that these tumors are significantly more proliferative, suggesting distinctive pathogenetic mechanisms. However, despite this higher proliferative activity, there was no significant difference in overall or failure-free survival between the t(14;18)-positive and -negative subsets within the GCB subgroup. Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy of mature B cells with an annual incidence of ϳ25,000 cases in the United States. DLBCL is a heterogeneous entity both clinically and morphologically. We have recently shown by gene expression profiling that DLBCL can be classified into two major subgroups. 1 The germinal center B-cell-like (GCB) subgroup expresses genes characteristic of normal GC B cells and is associated with a good outcome after multiagent chemotherapy, whereas the activated B-cell-like (ABC) subgroup expresses genes characteristic of activated blood B cells and is associated with a poor clinical outcome. Nonetheless, considerable molecular heterogeneity exists within each subgroup. A small number of DLBCL cases are unclassifiable and do not express the GCB or ABC sig-

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Section: Discussionmentioning

confidence: 99%

BCL2 Translocation Defines a Unique Tumor Subset within the Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

Iqbal

Sanger

Horsman

et al. 2004

The American Journal of Pathology

267

173

View full text Add to dashboard Cite

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“…28 However, CD40 signaling has been reported to prevent apoptosis in lymphocytes and in some tumors, such as bladder carcinomas. 2,3,12 The antiapoptotic effect of CD40 stimulation is based on evidence of transcriptional upregulation of a number of negative regulators of cell death, such as Bcl-x L , Bfl1 and A20, 29,30 and activation of phosphatidylinositol 3-kinase-Akt, 31 which could counteract in tumor cells a proapoptotic effect of CD154. 28 These apparently conflicting results may depend on cell type-specific signaling.…”

Section: Discussionmentioning

confidence: 99%

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

Bussolati

Russo

Deambrosis

et al. 2002

Intl Journal of Cancer

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CD40 activation by CD154 may trigger diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death, in normal and malignant cells. However, the pathophysiologic role of CD154 expressed by tumor cells remains unclear. We have investigated the expression of the CD40-CD154 system in 24 primary cultures derived from renal cell carcinomas, its correlation with tumor stage and its potential functional significance. We found coexpression of CD40 and CD154 in most of the renal carcinoma cell lines. CD154, but not CD40 expression, significantly correlated with tumor stage. Moreover, renal carcinoma cell lines also released the soluble form of CD154 into the supernatant. CD40 engagement by CD154 did not affect apoptosis or survival. On the contrary, CD154 stimulated cell proliferation, motility and production of PAF, a phospholipid mediator of inflammation with angiogenic properties. Key words: CD154; platelet-activating factor; renal carcinoma; CD40; angiogenesis CD154, the ligand of CD40, is a type II integral membrane protein, related to TNF and FasL. 1 Its receptor, CD40, is a 50 kDa transmembrane glycoprotein of the TNF superfamily, which is expressed in a multitude of different cell types, including B cells, monocytes, dendritic cells, endothelial cells, fibroblasts and renal epithelial cells. 2,3 CD40 was originally identified in a bladder carcinoma cell line, 4 and it is also expressed in a number of carcinomas, such as ovarian, nasopharyngeal, bladder, lung, colon and breast carcinomas, whereas normal nonproliferating tissues are CD40-negative. 5 CD40 engagement by CD154 conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and apoptosis. 6,7 The CD40 cytoplasmic C terminus lacks intrinsic kinase activity and adapter proteins of the TRAF family appear to mediate the activation of CD40-signaling cascades. 8 Despite the large interest, the functional role of CD40 in cancer development remains undetermined. CD40 appears to possess an opposite effect on tumor cell survival and apoptosis. CD40-mediated signaling has been reported to induce apoptosis when expressed in certain transformed cells of mesenchymal origin 9 and in carcinomas of the breast and lung. 10,11 Conversely, Jakobson et al. 12 demonstrated that CD40 stimulation inhibits Fas-mediated apoptosis in human bladder carcinoma cells and we showed a similar protective effect of CD40 in Kaposi's sarcoma cells. 13 Moreover, immunohistochemic studies revealed that detection of CD40 in primary cutaneous malignant melanoma might have negative prognostic value, suggesting its role in tumor progression. 14 CD154 is coexpressed with CD40 in melanoma cells and some carcinomas. 10,11,14 However, the pathophysiologic role of CD40 -CD154 interaction within the tumor cell remains unclear.In the present study, we investigated expression of the CD40 -CD154 system in 24 primary cultures derived from renal clear cell carcinomas, its correlation with tumor st...

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“…CD40 ligation in B cells induces a number of phenotypic changes similar to those observed upon LMP1 expression, including upregulation of CD23 and CD54 and induction of homotypic cell adhesion. In addition, both LMP1 and CD40 signalling result in up-regulation of the expression of certain anti-apoptotic proteins, such as A20 and members of the bcl-2 family, which may at least partly account for the survival advantage confered by CD40 engagement or LMP1 expression in normal B-cells (Henderson et al, 1991;Laherty et al, 1992;Rowe et al, 1994;Choi et al, 1995;Sarma et al, 1995). Studies from our and other laboratories have shown that CD40 is not only expressed in lymphoid cells but it is also present in normal, basal epithelial cells and in a number of carcinomas including ovarian, nasopharyngeal, bladder and breast (Stamenkovic et al, 1989;Young et al, 1989;Banchereau et al, 1994;Gallagher et al, manuscript in preparation), where its role remains widely unknown.…”

Section: Introductionmentioning

confidence: 99%

Epstein – Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors

et al. 1997

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Expression of the Epstein ± Barr virus (EBV) transforming LMP1 in B cells activates the transcription factor NF-kB and induces phenotypic changes through two distinct domains in the cytoplasmic C-terminus of the protein. The aa 187 ± 231 domain of LMP1, which is important for growth transformation, binds tumour necrosis factor (TNF) receptor associated factor (TRAF) 1 and TRAF3 and this interaction mediates subsequent signalling events. The TRAFs also associate with CD40, a member of the TNFR family, which upon ligation activates NF-kB and induces phenotypic changes similar to those mediated by LMP1. This study demonstrates that LMP1 expression in carcinoma cell lines and SV40-transformed keratinocytes results in induction of the pleiotropic cytokine interleukin 6 (IL6), an e ect which is also observed upon CD40 ligation. The mechanism by which either LMP1 expression or CD40 ligation induces IL6 production was found to be NF-kB-dependent. Mutational analysis identi®ed domains in the C-terminus of LMP1 which are important for NF-kB activation and IL6 secretion. LMP1 and CD40 share a common PxQxT core TRAF binding motif and mutations in or adjacent to this sequence impaired the ability of LMP1 or CD40 to induce NF-kB activation and IL6 secretion. The importance of TRAF interactions in mediating these e ects was con®rmed using dominant negative TRAF2 and TRAF3 mutants which also identi®ed di erences in the signalling events mediated by the two NF-kB activating domains of LMP1. A20, an anti-apoptotic protein which interacts with TRAF2 and blocks CD40-mediated NF-kB activity, also blocked NF-kB and IL6 secretion in LMP1-transfected epithelial cells. These results suggest that LMP1 regulates IL6 production in epithelial cells in a manner similar to CD40 ligation and implicate TRAFs as common mediators in the transduction of signals generated via the CD40 and LMP1 pathways. As a role for IL6 in regulating epithelial cell growth has previously been suggested, the control of IL6 secretion via the CD40 and LMP1 pathways may have implications for the growth of both normal and transformed epithelial cells.

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Activation of the B-cell Surface Receptor CD40 Induces A20, a Novel Zinc Finger Protein That Inhibits Apoptosis

Cited by 185 publications

References 28 publications

BCL2 Translocation Defines a Unique Tumor Subset within the Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

BCL2 Translocation Defines a Unique Tumor Subset within the Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

Epstein – Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors

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