Regulation of the Interleukin-7 Receptor α Promoter by the Ets Transcription Factors PU.1 and GA-binding Protein in Developing B Cells

DeKoter, Rodney P.; Schweitzer, Brock L.; Kamath, Meghana B.; Jones, Darrel; Tagoh, Hiromi; Bonifer, Constanze; Hildeman, David A.; Huang, Kuo Chan

doi:10.1074/jbc.m700377200

Cited by 54 publications

(38 citation statements)

References 41 publications

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“…Gene-targeting studies of the DNA binding GABP␣ subunit have revealed its critical roles during embryogenesis (25), during the reentry of the cell cycle (41), and in synaptic function at the neuromuscular junction (22,24). In the immune system, we and others showed that GABP critically regulates IL-7R␣ expression (5,38). Recently, we demonstrated that GABP is a key component of gene the regulatory network, programming B-lineage commitment and differentiation by directly regulating Pax5 gene expression (39).…”

Section: Vol 28 2008 Gabp␤1l Is Dispensable For Lymphocyte Developmmentioning

confidence: 99%

Targeting the GA Binding Protein β1L Isoform Does Not Perturb Lymphocyte Development and Function

Xue¹,

Jing²,

Bollenbacher-Reilley

et al. 2008

Molecular and Cellular Biology

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GA binding protein (GABP) is a ubiquitously expressed Ets family transcription factor that consists of two subunits, GABP␣ and GABP␤. GABP␣ binds to DNA, and GABP␤ heterodimerizes with GABP␣ and possesses the ability to transactivate target genes. Our previous studies using GABP␣-deficient mice revealed that GABP␣ is required for the development of both T and B cells. Two splice variants of GABP␤ are generated from the Gabpb1 locus and differ in their carboxy-terminal lengths and sequences. The longer isoform (GABP␤1L) can homodimerize and thus form ␣ 2 ␤ 2 tetramers depending on the gene context, whereas the shorter isoform (GABP␤1S) cannot. In this study, we generated mice that are deficient in GABP␤1L but that retain the expression of GABP␤1S. Surprisingly, GABP␤1L ؊/؊ mice had normal T-and B-cell development, and mature T and B cells showed normal responses to various stimuli. In contrast, targeting both GABP␤1L and GABP␤1S resulted in early embryonic lethality. Because of its incapability of forming homodimers, GABP␤1S has been suspected to have a dominant negative role in regulating GABP target genes. Our findings argue against such a possibility and rather suggest that GABP␤1S has a critical role in maintaining the transcriptional activity of the GABP␣/␤ complex.Ets family transcription factors have diverse functions in development, differentiation, apoptosis, and oncogenesis (15, 31). More than 30 Ets factors have been described, and all of them contain a conserved DNA binding Ets domain of approximately 85 amino acids in length. The Ets domain assumes a winged helix-loop-helix configuration and binds preferentially to a purine-rich consensus DNA sequence containing GGAA/T. GA binding protein (GABP) is the only Ets factor that functions as obligate multimeric proteins and consists of two unrelated subunits, GABP␣ and GABP␤ (26). GABP␣ harbors the Ets domain close to its C terminus and is thus responsible for DNA binding. GABP␤ cannot bind DNA but has transactivation activities. The interaction of these two subunits is mediated by the C terminus of GABP␣, including the ETS domain, and the ankyrin repeats at the N terminus of GABP␤.GABP was originally identified in studies of viral gene transcription (36, 37), but it is now known to regulate genes that control many basic cellular functions such as cellular respiration in mitochondria (30), protein components of ribosomes (10), and cell cycle progression (14, 32). A recent study using GABP␣-deficient fibroblasts demonstrated that GABP␣ is required for reentry into the cell cycle by regulating the expression of genes that are required for DNA synthesis (such as thymidylate synthase) and the degradation of cyclin-dependent kinase inhibitors (such as S-phase kinase-associated protein) (41). The observation that the inactivation of both Gabpa alleles resulted in death prior to implantation highlights its essential roles for early embryogenesis (25). In addition to these basic cellular functions, GABP regulates tissue-specific target genes, such as those encodi...

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Section: Vol 28 2008 Gabp␤1l Is Dispensable For Lymphocyte Developmmentioning

confidence: 99%

Targeting the GA Binding Protein β1L Isoform Does Not Perturb Lymphocyte Development and Function

Xue¹,

Jing²,

Bollenbacher-Reilley

et al. 2008

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…GABP␣ is part of a heterodimeric complex that includes GABP␤ (also known as NRF1) that can activate transcription and recruit histone acetyltransferases (30). In B cell progenitors, both GABP and PU.1 drive IL-7R␣ expression (28,31), but in thymocytes and naive T cells GABP alone performs this function (29). The reason behind the separation of functions of PU.1 and GABP in the different lymphocyte lineages is not clear.…”

mentioning

confidence: 99%

“…In addition, a few transcription factors have been identified that directly bind to and control Il7ra expression. Two transcription factors of the Ets family, PU.1 and GA binding protein ␣ (GABP␣; also known as NRF-2 and E4TF1-60), bind to the same site in the Il7ra promoter and activate its transcription (27)(28)(29). GABP␣ is part of a heterodimeric complex that includes GABP␤ (also known as NRF1) that can activate transcription and recruit histone acetyltransferases (30).…”

mentioning

confidence: 99%

Formation of IL-7Rαhigh and IL-7Rαlow CD8 T Cells during Infection Is Regulated by the Opposing Functions of GABPα and Gfi-1

Chandele

Joshi

Zhu

et al. 2008

The Journal of Immunology

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IL-7 is essential for the survival of naive and memory T cells, and IL-7 receptor α-chain (IL-7Rα) expression is dynamically regulated in activated CD8 T cells during acute viral and bacterial infections. Most virus-specific CD8 T cells become IL-7Rαlow and are relatively short-lived, but some escape IL-7Rα repression (referred to as IL-7Rαhigh memory precursor effector cells) and preferentially enter the memory CD8 T cell pool. How antiviral effector CD8 T cells regulate IL-7Rα expression in an “on and off” fashion remains to be characterized. During lymphocytic choriomeningitis virus infection, we found that opposing actions of the transcription factors GABPα (GA binding protein α) and Gfi-1 (growth factor independence 1) control IL-7Rα expression in effector CD8 T cells. Specifically, GABPα was required for IL-7Rα expression in memory precursor effector cells, and this correlated with hyperacetylation of the Il7ra promoter. In contrast, Gfi-1 was required for stable IL-7Rα repression in effector CD8 T cells and acted by antagonizing GABPα binding and recruiting histone deacetylase 1, which deacetylated the Il7ra promoter. Thus, Il7ra promoter acetylation and activity was dependent on the reciprocal binding of GABPα and Gfi-1, and these data provide a biochemical mechanism for the generation of stable IL-7Rαhigh and IL-7Rαlow states in virus-specific effector CD8 T cells.

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“…Several transcription factors that control Il7r gene expression have been identified. The promoter of Il7r contains binding sites for the PU.1 transcription factor, which is necessary for the IL-7R␣ expression in developing B cells (8,9). The same site is occupied in T cells by another ETS family transcription factor, GABP (10).…”

mentioning

confidence: 99%

CD8 Lineage-specific Regulation of Interleukin-7 Receptor Expression by the Transcriptional Repressor Gfi1

Ligons

Tuncer

Linowes

et al. 2012

Journal of Biological Chemistry

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Background: Expression of the IL-7R␣ gene is up-/down-regulated during T/B-lymphocyte development. Results: IL-7R␣ gene transcription is repressed by the transcription factor Gfi1, specifically in CD8 ϩ T-lymphocytes. Conclusion:Treatment by dexamethasone down-regulates Gfi1, which contributes to glucocorticoid receptor mediated upregulation of IL-7R expression. Significance: The mechanism by which the IL-7R gene gets turned on and off during development is a critical issue in biology. Interleukin-7 receptor ␣ (IL-7R␣) is essential for T cell survival and differentiation. Glucocorticoids are potent enhancers of IL-7R␣ expression with diverse roles in T cell biology.Here we identify the transcriptional repressor, growth factor independent-1 (Gfi1), as a novel intermediary in glucocorticoid-induced IL-7R␣ up-regulation. We found Gfi1 to be a major inhibitory target of dexamethasone by microarray expression profiling of 3B4.15 T-hybridoma cells. Concordantly, retroviral transduction of Gfi1 significantly blunted IL-7R␣ up-regulation by dexamethasone. To further assess the role of Gfi1 in vivo, we generated bacterial artificial chromosome (BAC) transgenic mice, in which a modified Il7r locus expresses GFP to report Il7r gene transcription. By introducing this BAC reporter transgene into either Gfi1-deficient or Gfi1-transgenic mice, we document in vivo that IL-7R␣ transcription is up-regulated in the absence of Gfi1 and down-regulated when Gfi1 is overexpressed. Strikingly, the in vivo regulatory role of Gfi1 was specific for CD8 ؉ , and not CD4 ؉ T cells or immature thymocytes. These results identify Gfi1 as a specific transcriptional repressor of the Il7r gene in CD8 T lymphocytes in vivo.

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Regulation of the Interleukin-7 Receptor α Promoter by the Ets Transcription Factors PU.1 and GA-binding Protein in Developing B Cells

Cited by 54 publications

References 41 publications

Targeting the GA Binding Protein β1L Isoform Does Not Perturb Lymphocyte Development and Function

Targeting the GA Binding Protein β1L Isoform Does Not Perturb Lymphocyte Development and Function

Formation of IL-7Rαhigh and IL-7Rαlow CD8 T Cells during Infection Is Regulated by the Opposing Functions of GABPα and Gfi-1

CD8 Lineage-specific Regulation of Interleukin-7 Receptor Expression by the Transcriptional Repressor Gfi1

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