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1.
J Immunol ; 180(3): 1694-703, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-18209066

ABSTRACT

The E2A gene encodes two E protein/class I basic helix-loop-helix transcription factors, E12 and E47, that are essential for B lymphopoiesis. In addition to the DNA-binding and protein dimerization domain, the E proteins share two highly conserved transcription activation domains. In this study, we show that both activation domains are required for optimal E2A-dependent transcription. Surprisingly, however, neither activation domain is required for E2A to rescue B lymphopoiesis from E2A(-/-) hemopoietic progenitors, although the N terminus of E2A, which harbors some transcription capacity, is required. Therefore, the E protein activation domains function redundantly in promoting B cell development. In contrast, the N-terminal activation domain, AD1, is required for a newly described ability of E2A to suppress macrophage development in vitro. Our findings demonstrate distinct functionalities for the E protein activation domains in B lymphocytes and macrophages.


Subject(s)
B-Lymphocytes/immunology , Basic Helix-Loop-Helix Transcription Factors/physiology , Lymphocyte Activation/genetics , Macrophage Activation/genetics , Macrophages/immunology , Transcriptional Activation , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , CD11b Antigen/analysis , Mice , Mice, Mutant Strains , Mutation , Protein Structure, Tertiary/physiology
2.
Blood ; 107(10): 4115-21, 2006 May 15.
Article in English | MEDLINE | ID: mdl-16449526

ABSTRACT

Loss of E2A transcription factor activity or activation of the intracellular form of Notch1 (ICN) leads to the development of leukemia or lymphoma in humans or mice, respectively. Current models propose that ICN functions by suppressing E2A through a pre-T cell receptor (TCR)-dependent mechanism. Here we show that lymphomas arising in E2A(-/-) mice require the activation of Notch1 for their survival and have accumulated mutations in, or near, the Notch1 PEST domain, resulting in increased stability and signaling. In contrast, lymphomas arising in p53(-/-) mice show the activation of Notch1, but no mutations were identified in ICN. The requirement for Notch1 signaling in E2A(-/-) lymphomas cannot be overcome by ectopic expression of pTalpha; however, pTalpha is required for optimal survival and expansion of these cells. Our findings indicate that the activation of Notch1 is an important "second hit" for the transformation of E2A(-/-) T cell lymphomas and that Notch1 promotes survival through pre-TCR-dependent and -independent mechanisms.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/deficiency , Lymphoma, T-Cell/immunology , Receptor, Notch1/genetics , Receptors, Antigen, T-Cell/immunology , Animals , Base Sequence , Blotting, Northern , Cell Survival , Cell Transformation, Neoplastic , DNA Primers , Humans , Lymphoma, T-Cell/pathology , Mice , Mice, Knockout , Tumor Suppressor Protein p53/deficiency
3.
J Exp Med ; 199(12): 1689-700, 2004 Jun 21.
Article in English | MEDLINE | ID: mdl-15210745

ABSTRACT

The basic helix-loop-helix transcription factors encoded by the E2A gene function at the apex of a transcriptional hierarchy involving E2A, early B cell factor (EBF), and Pax5, which is essential for B lymphopoiesis. In committed B lineage progenitors, E2A proteins have also been shown to regulate many lineage-associated genes. Herein, we demonstrate that the block in B lymphopoiesis imposed by the absence of E2A can be overcome by expression of EBF, but not Pax5, indicating that EBF is the essential target of E2A required for development of B lineage progenitors. Our data demonstrate that EBF, in synergy with low levels of alternative E2A-related proteins (E proteins), is sufficient to promote expression of most B lineage genes. Remarkably, however, we find that E2A proteins are required for interleukin 7-dependent proliferation due, in part, to a role for E2A in optimal expression of N-myc. Therefore, high levels of E protein activity are essential for the activation of EBF and N-myc, whereas lower levels of E protein activity, in synergy with other B lineage transcription factors, are sufficient for expression of most B lineage genes.


Subject(s)
B-Lymphocytes/immunology , DNA-Binding Proteins/immunology , Interleukin-7/immunology , Lymphopoiesis/immunology , Trans-Activators/immunology , Transcription Factors/immunology , Animals , Base Sequence , DNA Primers , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Genes, myc , Helix-Loop-Helix Motifs/immunology , Mice , Mice, Knockout , Molecular Sequence Data , TCF Transcription Factors , Trans-Activators/genetics , Transcription Factor 7-Like 1 Protein , Transcription Factors/deficiency , Transcription Factors/genetics
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