Ets-1 Regulates Plasma Cell Differentiation by Interfering with the Activity of the Transcription Factor Blimp-1

John, Shinu; Clements, James L.; Russell, Lisa; Garrett‐Sinha, Lee Ann

doi:10.1074/jbc.m705262200

Cited by 79 publications

(117 citation statements)

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“…Known to be involved in the pathogenesis of multiple human cancers, 12,13 both ETS1 and FLI1 have an important role in the development of lymphoid tissues and immune system control, [14][15][16] regulating the activity of important players in B-cell growth and maturation such as the B-cell-specific activator protein PAX5 17,18 and the master regulator of plasma cell differentiation, PRDM1. 19 Notably, Ets1 and Fli1 are repressed during the late phases of B-cell differentiation in an in vitro murine system. 20 Here, we show that the 11q24.3 genomic lesion correlates with high levels of ETS1 and FLI1 expression in human DLBCL primary samples.…”

Section: Introductionmentioning

confidence: 99%

“…This strongly indicated that ETS1 and FLI1 can cooperatively sustain cell viability in DLBCL ( Figure 3B). Because ETS factors are involved in B-cell differentiation and in the regulation of important players in GC differentiation, 17,19 we then evaluated whether ETS1 and FLI1 regulate the expression of known genes playing a key role in GC B-cell development in the OCI-Ly7 DLBCL cell line in order to elucidate the mechanisms through which ETS1 and FLI1 might exert their role in DLBCL. We analyzed the mRNA levels of BCL2, BCL6, PAX5, IRF4, PRDM1, and XBP1 following knocking-down of ETS1 and FLI1.…”

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confidence: 99%

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Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

Bonetti

Testoni

Scandurra

et al. 2013

Blood

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Key Points• A recurrent gain of a region of chromosome 11 (11q24.3) occurs in up to one-quarter of cases of diffuse large B-cell lymphoma.• ETS1 and FLI1 genes are overexpressed and determine proliferation, survival, and differentiation arrest of the lymphoma cells.Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. DLBCL is a heterogeneous disease characterized by different genetic lesions. We herein report the functional characterization of a recurrent gain mapping on chromosome 11q24.3, found in 23% of 166 DLBCL cases analyzed. The transcription factors ETS1 and FLI1, located within the 11q24.3 region, had significantly higher expression in clinical samples carrying the gain. Functional studies on cell lines showed that ETS1 and FLI1 cooperate in sustaining DLBCL proliferation and viability and regulate genes involved in germinal center differentiation. Taken together, these data identify the 11q24.3 gain as a recurrent lesion in DLBCL leading to ETS1 and FLI1 deregulated expression, which can contribute to the pathogenesis of this disease. (Blood. 2013;122(13):2233-2241) IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for 25% to 30% of adult cases in western countries, and it is characterized by heterogeneous histopathological, biological, and clinical features.1 DLBCL has been molecularly classified in at least 3 subtypes, reflecting different stages of B-cell differentiation: germinal center B-cell-like DLBCL (GCB) from germinal center (GC) centroblasts, activated B-cell-like DLBCL (ABC) from GC cells undergoing plasmacytic differentiation, and an intermediate type 3 DLBCL. 2 Physiological GC B-cell differentiation requires a complex transcriptional program and DLBCL displays recurrent genetic abnormalities that typically circumvent this normal genetic program, allowing the neoplastic B cells to avoid plasmacytic differentiation and evade apoptosis.2 Briefly, chromosomal translocations involving the BCL2 oncogene and mutations of the EZH2 methyltransferase are almost exclusively observed in GCB DLBCL, 3 whereas ABC DLBCL are preferentially associated with a disruption of terminal B-cell differentiation program (ie, PRDM1 inactivation and BCL6 deregulation) 4,5 and constitutive activation of the nuclear factor kB (NF-kB) transcription pathway (most commonly via somatic mutations of TNFAIP3, CARD11, CD79B, and MYD88). [6][7][8] Other recurrent lesions can be found in all the DLBCL subtypes, including inactivation of histone and/or chromatin modifying genes CREBBP, EP300, and MLL2 9,10 and of genes involved in immune recognition, such as b2-microglobulin and CD58. 11 It is likely that additional, undescribed genetic defects may also contribute to the pathogenesis of DLBCL.In the present study, aimed to identify new recurrent genetic defects in DLBCL, we performed genomic profiling analysis on 166 DLBCL samples, which enabled us to characterize a new recurrent lesion on chromosome 11q24.3 occurring in up to onequarter of...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

Bonetti

Testoni

Scandurra

et al. 2013

Blood

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“…The founding member of this family, Ets-1, is involved in numerous cellular mechanisms such as proliferation (de Nigris et al, 2001;Higuchi et al, 2007), differentiation (Lulli et al, 2006;John et al, 2007), migration (Kita et al, 2001), invasion (Taniguchi et al, 2007) and apoptosis (Teruyama et al, 2001). However, when overexpressed, Ets-1 is partly responsible for the development of invasive pathologies such as rheumatoid arthritis (Redlich et al, 2001), glomerulonephritis (Raffetseder et al, 2004) or cancers (Dittmer, 2003).…”

Section: Introductionmentioning

confidence: 99%

Ets-1 p27: a novel Ets-1 isoform with dominant-negative effects on the transcriptional properties and the subcellular localization of Ets-1 p51

et al. 2009

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The transcription factor Ets-1 is implicated in various physiological processes and invasive pathologies. We identified a novel variant of ets-1, ets-1D(III-VI), resulting from the alternative splicing of exons III to VI. This variant encodes a 27 kDa isoform, named Ets-1 p27. Ets-1 p27 lacks the threonine-38 residue, the Pointed domain and the transactivation domain, all of which are required for the transactivation of Ets-1 target genes. Both inhibitory domains surrounding the DNA-binding domain are conserved, suggesting that Ets-1 p27, like the full-length Ets-1 p51 isoform, is autoinhibited for DNA binding. We showed that Ets-1 p27 binds DNA in the same way as Ets-1 p51 does and that it acts both at a transcriptional and a subcellular localization level, thereby constituting a dual-acting dominant negative of Ets-1 p51. Ets-1 p27 blocks Ets-1 p51-mediated transactivation of target genes and induces the translocation of Ets-1 p51 from the nucleus to the cytoplasm. Furthermore, Ets-1 p27 overexpression represses the tumor properties of MDA-MB-231 mammary carcinoma cells in correlation with the known implication of Ets-1 in various cellular mechanisms. Thus the dual-acting dominant-negative function of Ets-1 p27 gives to the Ets-1 p27/Ets-1 p51 ratio a determining effect on cell fate.

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“…Both Blimp1 and Ets-1 are also expressed in B cells and counterregulate each other during the terminal differentiation of B cells to plasma cells (16,17). These observations raise the possibility that Blimp1 and Ets-1 also counterregulate each other in T cells, and that Ets-1 regulates the expression of IL-2 indirectly by suppressing Blimp1.…”

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confidence: 67%

Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter

Tsao

Tai

Tseng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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E26 transformation-specific sequence 1 (Ets-1), the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 by murine Th cells; however, its mechanism of action is still unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by primary human Th cells. Although Ets-1 negatively regulates the expression of Blimp1, a known suppressor of IL-2 expression, ablation of B lymphocyte-induced maturation protein 1 (Blimp1) does not rescue the expression of IL-2 by Ets-1-deficient Th cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) and is required for the recruitment of NFAT to the IL-2 promoter. In addition, Ets-1 is located in both the nucleus and cytoplasm of resting Th cells. Nuclear Ets-1 quickly exits the nucleus in response to calcium-dependent signals and competes with NFAT proteins for binding to protein components of noncoding RNA repressor of NFAT complex (NRON), which serves as a cytoplasmic trap for phosphorylated NFAT proteins. This nuclear exit of Ets-1 precedes rapid nuclear entry of NFAT and Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT.E 26 transformation-specific sequence 1 (Ets-1) is the founding member of the ETS family of transcription factors (1, 2); it is expressed mainly in lymphoid cells and plays multiple roles in regulating the development and function of these cells. Ets-1-deficient (KO) Th1 cells produce very little IL-2 (3). However, it is still unclear whether Ets-1 is also critical for the expression of IL-2 in human Th cells and how Ets-1 promotes the expression of IL-2.The transcriptional regulation of IL-2 has been characterized (4, 5). One of the positive regulators of IL-2 expression is the nuclear factor of activated T-cells (NFAT) family of transcription factors, which contains five members (6, 7). The promoter of the IL-2 gene contains five consensus binding sequences of NFAT (8). Deficiency of both NFATc1 and NFATc2 severely attenuates the expression of IL-2, confirming the critical role of NFATs in regulating IL-2 expression (9). In resting T cells, NFATs are phosphorylated and retained in cytoplasm by the NRON complex, which consists of a backbone of noncoding RNA called noncoding RNA repressor of NFAT (NRON) and several proteins, including Tnpo1, Iqgap1, chromosome segregation 1-like (Cse1l), protein phosphatase 2, regulatory subunit A, alpha (Ppp2r1a), and Psmd11 (10-12). The NRON complex serves as a cytoplasmic trap of NFAT. T-cell antigen receptor (TCR) signals and dephosphorylation of NFAT lead to the release of NFAT from the NRON complex. Free dephosphorylated NFAT is then translocated into the nucleus and transactivates IL-2 and many other genes. However, the detailed mechanism regulating the assembly/disassembly of the NRON complex and cytoplasmic/nuclear translocation of NFAT is still not fully understood.B lymphocyte-i...

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Ets-1 Regulates Plasma Cell Differentiation by Interfering with the Activity of the Transcription Factor Blimp-1

Cited by 79 publications

References 41 publications

Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

Ets-1 p27: a novel Ets-1 isoform with dominant-negative effects on the transcriptional properties and the subcellular localization of Ets-1 p51

Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter

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