Displacement of an E-box-binding repressor by basic helix-loop-helix proteins: implications for B-cell specificity of the immunoglobulin heavy-chain enhancer.

Abstract

The activity of the immunoglobulin heavy-chain (IgH) enhancer is restricted to B cells, although it binds both B-cell-restricted and ubiquitous transcription factors. Activation of the enhancer in non-B cells upon overexpression of the basic helix-loop-helix (bHLH) protein E2A appears to be mediated not only by the binding of E2A to its cognate E box but also by the resulting displacement of a repressor from that same site.We have identified a "two-handed" zinc finger protein, denoted ZEB, the DNA-binding specificity of which mimics that of the cellular repressor. By employing a derivative E box that binds ZEB but not E2A, we have shown that the repressor is active in B cells and the IgH enhancer is silenced in the absence of binding competition by bHLH proteins. Hence, we propose that a necessary prerequisite of enhancer activity is the B-cell-specific displacement of a ZEB-like repressor by bHLH proteins.

Inhibition of ZEB1 by miR-200 characterizes Helicobacter pylori-positive gastric diffuse large B-cell lymphoma with a less aggressive behavior

“…6,7 Although studies on ZEB1 focus mostly on its roles in epithelial-mesenchymal transition and metastasis, it is becoming evident that ZEB1 is also critical in the development of hematopoietic cells, including both B cells and T cells. For the B-lineage, ZEB1 may inhibit BCL6, the master transcription factor for the formation of germinal center B cells, 8 and is required for the normal development of marginal zone B cells and the production of immunoglobulin M. 9,10 Consistent with these data, overexpression of ZEB1 induces a more aggressive behavior of diffuse large B-cell lymphoma of the lymph nodes. 11 For the T-lineage, ZEB1 regulates T-cell development.…”

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

“…This zinc-finger transcription factor was initially identified as a transcriptional repressor of the immunoglobulin heavy chain enhancer in B-cells, acting through E-boxes (Genetta et al, 1994). Zeb1 can also bind the CDH1 promoter, thereby repressing its transcription and deregulating the epithelial phenotype of breast cancer cells (Eger et al, 2005).…”

DNA binding of USF is required for specific E-box dependent gene activation in vivo

“…Speci®c mutations in the prothymosin-a gene allow activation by TFE-3; similarly, mutations in the IgH enhancer allow activation by TFE-3 in non B-cells, demonstrating that TFE-3 is actively prevented from activating these genes in vivo (Desbarats et al, 1996;Genetta et al, 1994). We now demonstrate that DNA binding by USF is required for inhibiting transactiva-tion by TFE-3 in vivo.…”

“…Previous work has shown that ectopic expression of TFE-3 failed to activate the IgH or prothymosin-a enhancers; in both cases, a mutation in a second E-box element close to the TFE-3 binding site relieved the restriction, suggesting that factors binding to these elements actively prevent transcriptional activation by TFE-3 (Desbarats et al, 1996;Genetta et al, 1994) (Figure 1a). In order to test whether this restriction targets the transcriptional activation domain of TFE-3, we generated a chimeric protein that carries the transactivation domain of the viral Vp16 protein and a nuclear localization signal of SV40 large T antigen fused to the open reading frame of TFE-3 (Figure 1b).…”

“…In analogy to the situation of prothymosin-a, TFE-3 is unable to activate the enhancer in non B-cells due to the presence of an inhibitory E-box (E5) (Genetta et al, 1994) (see Figure 1a).…”