E2A and E2-2 are subunits of B-cell-specific E2-box DNA-binding proteins.

Bain, Gretchen; Gruenwald, Stefan; Murre, C

doi:10.1128/mcb.13.6.3522

Cited by 136 publications

(112 citation statements)

References 27 publications

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“…In particular, E-proteins are crucial for development of lymphoid progenitors to the B-and T-cell lineages [26]. In the development of T cells, both E2A and HEB have been implicated [30][31][32]. E12 and E47 are essential for B-cell development by controlling either directly or indirectly the expression of Pax-5, a factor essential for B-cell lineage fate decision and securing of the B-cell identity until the mature stages of development [33][34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix‐loop‐helix factor E2‐2 and the Ets factor Spi‐B

et al. 2008

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Plasmacytoid dendritic cells (pDC) are central players in the innate and adaptive immune response against viral infections. The molecular mechanism that underlies pDC development from progenitor cells is only beginning to be elucidated. Previously, we reported that the Ets factor Spi-B and the inhibitors of DNA binding protein 2 (Id2) or Id3, which antagonize E-protein activity, are crucially involved in promoting or impairing pDC development, respectively. Here we show that the basic helix-loop-helix protein E2-2 is predominantly expressed in pDC, but not in their progenitor cells or conventional DC. Forced expression of E2-2 in progenitor cells stimulated pDC development. Conversely, inhibition of E2-2 expression by RNA interference impaired the generation of pDC suggesting a key role of E2-2 in development of these cells. Notably, Spi-B was unable to overcome the Id2 enforced block in pDC development and moreover Spi-B transduced pDC expressed reduced Id2 levels. This might indicate that Spi-B contributes to pDC development by promoting E2-2 activity. Consistent with notion, simultaneous overexpression of E2-2 and Spi-B in progenitor cells further stimulated pDC development. Together our results provide additional insight into the transcriptional network controlling pDC development as evidenced by the joint venture of E2-2 and Spi-B.Key words: E2-2/TCF4 Á E-proteins Á Human development Á Plasmacytoid dendritic cell Á Spi-B Supporting Information available online See accompanying commentary by Esashi and Liu IntroductionThe ability of dendritic cells (DC) to capture and present antigenic peptides has established a function in both the adaptive and innate branches of the immune system. Extensive characterization of DC has revealed the existence of many different DC subsets with distinct cell surface phenotype, cytokine expression profile, and anatomical localization [1]. One member of the DC family is the plasmacytoid DC (pDC), which is hallmarked by their capacity to produce high levels of type I interferons and hence are also known as natural type I interferons producing cells [2]. Eur. J. Immunol. 2008. 38: 2389-2400 DOI 10.1002 HIGHLIGHTS 2389Frontline pDC are detected in blood and most tissues, including spleen, lymph nodes, and thymus [2,3]. Previously, we described that at least two developmental pathways exist for pDC, an extrathymic and an intrathymic pathway [4]. The requirements for the development of DC subsets are not fully understood. In mice it has been shown that conventional DC (cDC) and pDC can develop from minor Flt3 1 subpopulations within the common myeloid and the common lymphoid progenitor pools [5][6][7]. Recently, this pool was narrowed down to a DC committed precursor (pro-DC) that can only develop into cells of the DC lineages [8,9]. It is not clear yet at what point in DC development the commitment to a subpopulation is accomplished. Also, human pDC can be derived from both myeloid and lymphoid progenitor cells [10,11]. A better understanding of the molecular mechanisms that control...

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Section: Discussionmentioning

confidence: 99%

Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix‐loop‐helix factor E2‐2 and the Ets factor Spi‐B

et al. 2008

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“…The exclusive presence of E2a promoter insertions in tumors with Em-driven transoncogenes excludes a role for E2a as a dominant oncogene. Together with the notion that E2a is known to induce transcription of the immunoglobulin chains via binding to their regulatory E boxes (Murre et al, 1989;Bain et al, 1993;Shen and Kadesch, 1995) it however suggests that E2a insertions exert their oncogenic effect through altered expression of the transgene. This would be in line with our observation that proviral activations of E2a are early events in tumor initiation rather than tumor progression, and also explain the E2a insertion in the EmPim1 tumor, since it is known that the oncogenic potential of Pim1 is strongly dose-dependent (Domen et al, 1993;van der Lugt et al, 1995;Allen et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

Proviral activation of the tumor suppressor E2a contributes to T cell lymphomagenesis in EμMyc transgenic mice

2002

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The basic helix -loop -helix factor E2A plays an important role in the development of B and T lymphocytes. In addition, E2a has been implicated as a gene with tumor suppressor activity, since mice deficient for E2a succumb to T cell lymphomas. We have performed retroviral tagging in EmMyc transgenic mice to identify genes that contribute to lymphomagenesis. The EmMyc transgenic mouse is a well-established model of a common translocation in human B cell lymphomas. Analyses of the proviral insertion sites in the MuLVinduced lymphomas revealed that a number of T cell lymphomas carried proviral insertions in the promoter region of E2a. These proviral insertions yield hybrid viral-E2a mRNAs resulting in a marked rise in E2A protein levels. The proviral insertions in E2a were predominantly of clonal origin indicating that E2a insertions are early events in these T cell lymphomas. The primary oncogenic effect of E2A is likely to be associated with enhancement of transcription of the cMyc transgene via binding to the regulatory immunoglobulin enhancers. The results herein thus provide the first evidence that in a specific setting E2A overexpression can contribute to T-lymphomagenesis. This implies that E2a contains oncogenic features in addition to the previously described tumor suppressive properties.

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“…E12 and E47, that are different splicing products of the E2A gene bind these sites in B cells, although homodimers of E47 appear to be the predominant transcriptionally active form (Bain et al, 1993;Shen and Kadesch, 1995). To assess nuclear levels of E2A proteins we used Western blotting with an antibody raised against amino acid 1-649 representing full-length E47 protein of human origin ( Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma

et al. 2002

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In classical Hodgkin lymphoma the malignant Hodgkin/ Reed-Sternberg (HRS) cells characteristically constitute only a small minority of the tumour load. Their origin has been debated for decades, but on the basis of rearrangement and somatic hypermutations of their immunoglubulin (Ig) genes, HRS cells are now ascribed to the B-cell lineage. Nevertheless, phenotypically HRS cells have lost their B cell identity: they usually lack common B cell-specific surface markers such as CD19 and CD79a as well as Ig gene transcripts. Here we demonstrate that Ig promoters as well as both intronic and 3' enhancer sequences are transcriptionally inactive in HRS cell lines. This inactivity correlates with either reduced levels or even a complete lack of several B cellspecific transcription factors required for their expression: Oct-2, OBF-1, PU.1, E47/E12, PAX-5 and EBF. Moreover, we demonstrate that PU.1 and PAX-5 are significantly down-regulated in HRS cells in pathological specimens from primary tumour tissues. However, forced expression of these transcription factors can activate regulatory sequences of silenced B cell marker genes, and in one instance also transcription from a silenced endogenous locus. Thus, HRS cells are dedifferentiated B cells with global down-regulation of B cell-specific genes.

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E2A and E2-2 are subunits of B-cell-specific E2-box DNA-binding proteins.

Cited by 136 publications

References 27 publications

Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix‐loop‐helix factor E2‐2 and the Ets factor Spi‐B

Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix‐loop‐helix factor E2‐2 and the Ets factor Spi‐B

Proviral activation of the tumor suppressor E2a contributes to T cell lymphomagenesis in EμMyc transgenic mice

Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma

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