The Transcription Factor GABP Is a Critical Regulator of B Lymphocyte Development

Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1674, USA.
Immunity (Impact Factor: 21.56). 05/2007; 26(4):421-31. DOI: 10.1016/j.immuni.2007.03.010
Source: PubMed


GA binding protein (GABP) is a ubiquitously expressed Ets-family transcription factor that critically regulates the expression of the interleukin-7 receptor alpha chain (IL-7Ralpha) in T cells, whereas it is dispensable for IL-7Ralpha expression in fetal liver B cells. Here we showed that deficiency of GABPalpha, the DNA-binding subunit of GABP, resulted in profoundly defective B cell development and a compromised humoral immune response, in addition to thymic developmental defects. Furthermore, the expression of Pax5 and Pax5 target genes such as Cd79a was greatly diminished in GABPalpha-deficient B cell progenitors, pro-B, and mature B cells. GABP could bind to the regulatory regions of Pax5 and Cd79a in vivo. Thus, GABP is a key regulator of B cell development, maturation, and function.

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Available from: Xuefang Jing, Mar 19, 2014
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    • "In previous studies, GABP was shown to regulate the expression of various crucial haematopoietic genes, e.g. paired box 5 (PAX5) [13], interleukin 7 receptor (IL7R) [12], neutrophil elastase (ELANE) [14], and integrin beta 2 (ITGB2/CD18) [15] [16] [17], which encodes the beta chain of leukocyte-specific integrins, e.g. macrophage antigen 1 (Mac-1). "
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    ABSTRACT: The heteromeric transcription factor GA-binding protein (GABP) consists of two subunits, the alpha subunit (GABPA) carrying the DNA-binding ETS domain, and the beta subunit (GABPB1) harbouring the transcriptional activation domain. GABP is involved in haematopoietic stem cell maintenance and differentiation of myeloid and lymphoid lineages in mice. To elucidate the molecular function of GABP in human haematopoiesis, the present study addressed effects of ectopic overexpression of GABP focussing on the myeloid compartment. Combined overexpression of GABPA and GABPB1 caused a proliferation block in cell lines and drastically reduced the colony-forming capacity of murine lineage-negative cells. Impaired proliferation resulted from perturbed cellular cycling and induction of myeloid differentiation shown by surface markers and myelomonocytic morphology of U937 cells. Depending on the dosage and functional integrity of GABP, ITGAM expression was induced. ITGAM encodes CD11b, the alpha subunit of integrin Mac-1, whose beta subunit, ITGB2/CD18, was already described to be regulated by GABP. Finally, Shield1-dependent proteotuning, luciferase reporter assays and chromatin immunoprecipitation showed that GABP activates the ITGAM/CD11b promoter via three binding sites close to the translational start site. In conclusion, the present study supports the crucial role of GABP in myeloid cell differentiation and identified ITGAM/CD11b as a novel GABP target gene. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 07/2015; 1849(9). DOI:10.1016/j.bbagrm.2015.07.005 · 4.66 Impact Factor
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    • "Genes associated with mitochondrial function and regulated by nuclear respiratory factors can be bound and activated by NRF-1 (e.g., human cytochrome c), by NRF-2 (e.g., mouse cytochrome oxidase subunit IV), or both (e.g., human succinate dehydrogenase subunit B). Genes other than those involved in mitochondrial biogenesis and respiration have also been shown to be regulated by NRF-1 and NRF-2, such as the human FMR1 gene associated with fragile X syndrome [53]; reported functions of NRF-2/GABP include regulating B lymphocyte and myeloid development [52], [54], cell cycle progression [55], and formation of neuromuscular junctions [56]. Overall, our analysis has shown that multiple regulatory regions within the imprinted AS/PWS domain are bound by nuclear respiratory factors and/or YY1. "
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    ABSTRACT: The Angelman/Prader-Willi syndrome (AS/PWS) domain contains at least 8 imprinted genes regulated by a bipartite imprinting center (IC) associated with the SNRPN gene. One component of the IC, the PWS-IC, governs the paternal epigenotype and expression of paternal genes. The mechanisms by which imprinting and expression of paternal genes within the AS/PWS domain - such as MKRN3 and NDN - are regulated by the PWS-IC are unclear. The syntenic region in the mouse is organized and imprinted similarly to the human domain with the murine PWS-IC defined by a 6 kb interval within the Snrpn locus that includes the promoter. To identify regulatory elements that may mediate PWS-IC function, we mapped the location and allele-specificity of DNase I hypersensitive (DH) sites within the PWS-IC in brain cells, then identified transcription factor binding sites within a subset of these DH sites. Six major paternal-specific DH sites were detected in the Snrpn gene, five of which map within the 6 kb PWS-IC. We postulate these five DH sites represent functional components of the murine PWS-IC. Analysis of transcription factor binding within multiple DH sites detected nuclear respiratory factors (NRF's) and YY1 specifically on the paternal allele. NRF's and YY1 were also detected in the paternal promoter region of the murine Mrkn3 and Ndn genes. These results suggest that NRF's and YY1 may facilitate PWS-IC function and coordinately regulate expression of paternal genes. The presence of NRF's also suggests a link between transcriptional regulation within the AS/PWS domain and regulation of respiration. 3C analyses indicated Mkrn3 lies in close proximity to the PWS-IC on the paternal chromosome, evidence that the PWS-IC functions by allele-specific interaction with its distal target genes. This could occur by allele-specific co-localization of the PWS-IC and its target genes to transcription factories containing NRF's and YY1.
    PLoS ONE 02/2013; 8(2):e52390. DOI:10.1371/journal.pone.0052390 · 3.23 Impact Factor
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    • "The GA binding protein (GABP) complex, consisting of DNAbinding GABPa subunit and transactivation GABPb subunit, has been known to critically regulate cell cycle control, protein synthesis, and cellular metabolism (Rosmarin et al., 2004), as evidenced by early lethality upon germline deletion of GABPa (Ristevski et al., 2004; Xue et al., 2004). Conditional targeting studies also revealed that GABPa has cell-type-specific roles in myeloid cells, as well as in T and B lymphocytes (Xue et al., 2007; Yang et al., 2011; Yu et al., 2010). Whereas GABPa is encoded by a single Gabpa gene, GABPb exists in three different isoforms: GABPb1L and GABPb1S are splice variants from the Gabpb1 gene, and GABPb2 is produced from the Gabpb2 gene (de la Brousse et al., 1994; LaMarco et al., 1991). "
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    ABSTRACT: Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) are both capable of self-renewal, with HSCs sustaining multiple blood lineage differentiation and LSCs indefinitely propagating leukemia. The GABP complex, consisting of DNA binding GABPα subunit and transactivation GABPβ subunit, critically regulates HSC multipotency and self-renewal via controlling an essential gene regulatory module. Two GABPβ isoforms, GABPβ1L and GABPβ2, contribute to assembly of GABPα(2)β(2) tetramer. We demonstrate that GABPβ1L/β2 deficiency specifically impairs HSC quiescence and survival, with little impact on cell cycle or apoptosis in differentiated blood cells. The HSC-specific effect is mechanistically ascribed to perturbed integrity of the GABP-controlled gene regulatory module in HSCs. Targeting GABPβ1L/β2 also impairs LSC self-renewal in p210(BCR-ABL)-induced chronic myelogenous leukemia (CML) and exhibits synergistic effects with tyrosine kinase inhibitor imatinib therapy in inhibiting CML propagation. These findings identify the tetramer-forming GABPβ isoforms as specific HSC regulators and potential therapeutic targets in treating LSC-based hematological malignancy.
    Cell stem cell 08/2012; 11(2):207-19. DOI:10.1016/j.stem.2012.05.021 · 22.27 Impact Factor
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