The Role of MAPKs in B Cell Receptor-induced Down-regulation of Egr-1 in Immature B Lymphoma Cells

Abstract

The immediate-early gene egr-1 (also known as NGFI-A, krox24, zif268, and tis8) encodes a transcription factor containing three tandem zinc finger motifs that bind to GC-rich DNA elements in the promoters of a range of target genes to activate their transcription (1). egr-1 expression is elicited in response to a diverse variety of signals, including growth factors, cytokines, lipopolysaccharide, serum, irradiation, stress, hypoxia, and urea, in many cell types, including neuronal cells, epithelial cells, fibroblasts, myeloid cells, and T and B lymphocytes (2-9). In many studies, Egr-1 was found to be associated with cell proliferation, differentiation, and transformation (3, 10 -14). Egr-1 was also shown to induce apoptosis in certain cell types in response to irradiation by activating p53 (15) or PTEN expression (16). Yu et al. (17) reported that differential post-translational modification of Egr-1 (acetylation versus phosphorylation) is likely responsible for its different roles in promoting growth versus apoptosis in response to serum and UV irradiation. Moreover, Egr-1 is shown to be important for production of pro-inflammatory cytokines such as interleukin-1␤, interleukin-13, and tumor necrosis factor as well as chemokines (18 -20).In normal mature B lymphocytes, signaling through the B cell receptor (BCR) 2 induces rapid and transient expression of egr-1 (6), but its importance for subsequent B cell activation and proliferation is unknown. In contrast, BCR engagement in immature B lymphoma cells fails to induce egr-1 expression, and the lymphoma cells undergo growth inhibition and apoptosis (21). Thus, BCR-induced positive versus negative signals are reflected in the differential expression of egr-1. Interestingly, an immature B lymphoma cell line (BKS-2) constitutively expresses high levels of Egr-1, and antisense oligodeoxynucleotides (ODNs) to Egr-1 inhibit BKS-2 cell growth (14). BCR signaling, which causes growth arrest and apoptosis of BKS-2 cells, also down-regulates egr-1 (14). The down-regulation of Egr-1 and growth inhibition caused by anti-IgM antibody are reversed by CpG ODN (22). These data suggest a positive correlation between the levels of Egr-1 and growth of B lymphoma cells. An examination of the microarray data published by Alizadeh et al. (23) revealed that egr-1 expression is elevated in ϳ35% of human diffuse large B lymphoma cells, supporting the notion that Egr-1 is important for B lymphoma cell growth.Several studies in different cell lines have shown that the rapid induction of Egr-1 with various stimuli is mediated * This work was supported by National Institutes of Health Grant 5P01CA092372 (to S. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.

A shared gene expression signature in mouse models of EBV-associated and non–EBV-associated Burkitt lymphoma

“…by guest www.bloodjournal.org From involved in cell survival, growth, and differentiation [32][33][34] suggested to us that Egr1 may be important for the ability of LMP2A to accelerate tumor onset in the presence of deregulated MYC. That Egr1 induction is downstream of BCR signaling 24,33,38 and LMP2A can be described as a BCR signaling "mimic" leant further support to our hypothesis. However, Egr1 function, at least the amount that could be blocked by expression of a dominant negative Egr, 24 does not appear to be required for tumor acceleration by LMP2A ( Figure 5).…”

“…32,[35][36][37] In B cells, Egr1 is induced by BCR signaling. 24,33,38 Given that LMP2A is a signaling molecule that is functionally similar to the BCR, 10,11,22 we hypothesized that induction of Egr1 in LMP2A/-MYC mice may contribute to their accelerated tumorigenesis. 20,21 To test the functional importance of Egr1 in our transgenic model, we used a transgenic mouse expressing a DN Egr in B cells.…”

“…31 The Egr1 gene encodes a transcription factor expressed in many cell types whose function depends on cell type and context; Egr1 is known to function in cell differentiation, growth promotion and growth suppression, and apoptosis. [32][33][34] Egr1 belongs to the immediate early gene family and is rapidly induced in response to various stimuli, including growth factors, cytokines, and irradiation, varying by cell type. 32,[35][36][37] In B cells, Egr1 is induced by BCR signaling.…”

Novel Pro-survival Functions of the Kruppel-like Transcription Factor Egr2 in Promotion of Macrophage Colony-stimulating Factor-mediated Osteoclast Survival Downstream of the MEK/ERK Pathway

“…Egr1 up-regulation in prostate cancer cells is thought to promote cell growth and transformation through increased expression of cyclin D1 (15,16). However, Egr1 expression is either down-regulated or promotes apoptosis in other cancer cell lines (17)(18)(19), indicating cell-type specific responses. Egr2 expression has been primarily reported to promote apoptosis through transactivation of p53, FasL, Bak, and BNIP3 or suppress proliferation through PTEN expression (20 -22).…”

Activated Protein C Decreases Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand by an EPCR- Independent Mechanism Involving Egr-1/Erk-1/2 Activation

“…19 Of interest, EGR-1 function has been shown to be dependent on ERK1/2 phosphorylation. 20 APC is a serine protease with a well characterized anticoagulant activity. Recent studies have demonstrated that APC has antiinflammatory and cytoprotective activities, which are not attributed to the anticoagulant activity of APC.…”