Early Growth Response Genes Regulate B Cell Development, Proliferation, and Immune Response

Abstract

Egr-1 (early growth response gene-1) is an immediate early gene encoding a zinc finger motif-containing transcription factor. Upon cross-linking of BCR, mature B cells undergo proliferation with an increase in Egr-1 message. Immature B lymphoma cells that express Egr-1 message and protein constitutively are growth inhibited when Egr-1 is down-regulated by negative signals from BCR or by antisense oligonucleotides. To test the hypothesis that Egr-1 is important for B cell development, we examined B cells from primary and secondary lymphoid organs in Egr-1−/− mice. Marginal zone B cell development was arrested in these mice, whereas the B cells in all other compartments were increased. To test the hypothesis that Egr-1 function may be partially compensated by other Egr family members, we developed transgenic mice expressing a dominant negative form of Egr-1, which lacks the trans activation domain but retains the DNA-binding domain, in a B cell-specific manner. There was a decrease in B lymphopoiesis in the bone marrow accompanied by a reduction in splenic immature and mature B cells as well as marginal zone B cells in the transgenic mice. Moreover, transgenic mice respond poorly to BCR cross-linking in vitro and T-independent and T-dependent Ags in vivo.

Cellular Immediate-Early Gene Expression Occurs Kinetically Upstream of Epstein-Barr Virus bzlf1 and brlf1 following Cross-Linking of the B Cell Antigen Receptor in the Akata Burkitt Lymphoma Cell Line

“…Furthermore, EGR1 protein expression decays while ZEBRA protein expression increases. While it is known that EGR1 is expressed downstream of activation of the B cell antigen receptor (22), a novel aspect of our study was to demonstrate that expression of several cellular IE genes, including egr1, was kinetically upstream of bzlf1 and brlf1 ( Fig. 5; Table 2).…”

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

“…Double transgenic mice were generated by crossing the Tg6-LMP2A line with previously characterized -MYC mice 18 and dominant negative Egr1 (DN Egr) transgenic mice. 24 Mice were sacrificed when cervical lymph node tumors could be observed externally and mice were moribund. Animals were maintained at Northwestern University's Center for Comparative Medicine, in accordance with University animal welfare guidelines, and approval was granted by the Northwestern University Animal Care and Use Committee.…”

“…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.…”

“…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. 24 The DN Egr used in our studies consists of a truncated version of the Egr1 protein, containing only the DNA binding domain, which is expressed from an Ig promoter, targeting expression to B cells. The dominant negative has been shown to inhibit the functions of all Egr family members and subtly alter B-cell differentiation and responses to BCR ligation.…”

“…The dominant negative has been shown to inhibit the functions of all Egr family members and subtly alter B-cell differentiation and responses to BCR ligation. 24 We generated triple transgenic mice expressing LMP2A, MYC, and DN Egr in B cells. LMP2A/-MYC/DN Egr mice and -MYC/DN Egr mice both develop lymph node tumors, and these tumors contain similar levels of DN Egr mRNA ( Figure 5A).…”