Proteins of the ETS family with transcriptional repressor activity

Mavrothalassitis, George; Ghysdael, Jacques

doi:10.1038/sj.onc.1204045

Cited by 135 publications

(96 citation statements)

References 106 publications

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“…Therefore, we have proposed that MBF1 is a cellular repressor factor whose activity is abrogated in permissive cells. To date, most mammalian ets family members function as transcriptional activators (for reviews see Dittmer & Nordheim, 1998, Mavrothalassitis & Ghysdael, 2000, which is not in keeping with the proposed role of MBF1 in the repression of the MIEP. However, Sgouras et al (1995) have identified a factor, ERF, as an ets family member that functions as a transcriptional repressor.…”

Section: Results Erf Physically Interacts With the Miep In Vitromentioning

confidence: 99%

Ets-2 Repressor Factor (ERF) mediates repression of the human cytomegalovirus major immediate-early promoter in undifferentiated non-permissive cells

Bain

Mendelson

Sinclair

2003

Journal of General Virology

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The repression of human cytomegalovirus immediate-early (IE) lytic gene expression is crucial for the maintenance of the latent viral state. By using conditionally permissive cell lines, which provide a good model for the differentiation state-dependent repression of IE gene expression, we have identified several cellular factors that bind to the major immediate-early promoter (MIEP) and whose expression is down-regulated after differentiation to a permissive phenotype. Here we show that the cellular protein Ets-2 Repressor Factor (ERF) physically interacts with the MIEP and represses MIEP activity in undifferentiated non-permissive T2 embryonal carcinoma cells. This factor binds to the dyad element and the 21 bp repeats within the MIEP -regions known to be important for the negative regulation of MIEP activity. Finally, we show that following differentiation to a permissive phenotype ERF's repressive effects are severely abrogated. INTRODUCTIONHuman cytomegalovirus (HCMV) is a betaherpesvirus whose sero-prevalence can vary from 50 to 90 % depending on the socio-economic status of the population. Following primary infection, which rarely causes disease in the immunocompetent, HCMV maintains a latent infection throughout the lifetime of the infected host. However, infection or reactivation in the immunocompromised, such as transplant recipients or AIDS patients, is associated with morbidity and mortality (reviewed in Alford & Britt, 1993).Productive HCMV infection and reactivation require an ordered cascade of gene expression and are dependent on the expression of the immediate-early (IE) gene products IE72 and IE86 (also known as IE1 and IE2 respectively). These IE proteins are potent and promiscuous transactivators of both cellular and viral genes, and serve to activate the viral early (E) gene promoters (Pizzorno et al., 1988;Malone et al., 1990), ultimately leading to viral DNA replication, expression of the viral late (L) genes and virus assembly. The expression of IE72 and IE86 is under the control of the major immediate-early promoter (MIEP), a highly complex region comprising a TATA box, an upstream imperfect dyad symmetry element (also termed the modulator), and an extremely powerful enhancer region made up of a series of 17, 18, 19 and 21 bp repeat motifs (reviewed in Meier & Stinski, 1996). MIEP activity is regulated by a myriad of positively and negatively acting cellular and viral proteins. For example, there are numerous nuclear factor-1 (NF-1) sites within the MIEP and the 18 and 19 bp repeat sequences contain NF-kB and cyclic AMPresponsive element binding protein (CREB) binding sites respectively (Meier & Stinski, 1996). Conversely, several studies using non-permissive cells have shown that the modulator and the 21 bp repeats are responsible for the inhibition of MIEP activity in such cells (Nelson et al., 1987;Lubon et al., 1989;Kothari et al., 1991).In vivo, monocytes have been identified as an important site of HCMV latency (Taylor-Wiedeman et al., 1991); these cells carry the viral genome in t...

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Section: Results Erf Physically Interacts With the Miep In Vitromentioning

confidence: 99%

Ets-2 Repressor Factor (ERF) mediates repression of the human cytomegalovirus major immediate-early promoter in undifferentiated non-permissive cells

Bain

Mendelson

Sinclair

2003

Journal of General Virology

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“…RTK/ Ras/MAPK signaling results in the phosphorylation of both transcription factors, inactivating Yan and stimulating PntP2, thus both derepressing and activating target gene expression (Brunner et al 1994;O'Neill et al 1994;Rebay and Rubin 1995;Gabay et al 1996;Flores et al 2000;Halfon et al 2000;Xu et al 2000;Baker et al 2001). The vertebrate Ets repressor protein ERF, which is excluded from the nucleus in response to Ras/MAPK signaling, may serve a function analogous to that of Yan (Mavrothalassitis and Ghysdael 2000).…”

Section: Default Repression In Rtk Signalingmentioning

confidence: 99%

“…Two Ets transcription factors, mouse Net and goldfish GETS-1, act as constitutive repressors, but are converted to direct transcriptional activators by Ras/MAPK signaling ( Fig. 4D; for review, see Mavrothalassitis and Ghysdael 2000). In several developmental contexts in Drosophila, two MAPK-regulated Ets proteins, the Yan repressor and the PntP2 activator, function in what appears to be a Type II transcriptional switch (Fig.…”

Section: Default Repression In Rtk Signalingmentioning

confidence: 99%

Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling

Barolo¹,

Posakony²

2002

Genes Dev.

431

345

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“…Ets-2 is a member of the ETS family of transcription factors that bind to purine-rich DNA sequences with GGA(A/T) as a central core consensus through a highly conserved DNA binding domain (13,14). Ets proteins function as activators or repressors of transcription in partnership with other DNA-binding proteins and coregulators and control the expression of genes involved in diverse biological functions, such as mitosis, growth, development, differentiation, apoptosis, and regulation of immunity (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Ets-2 plays an important role in the maturation, proliferation, and survival of mouse thymocytes, possibly by regulating the expression of c-Myc (23).…”

mentioning

confidence: 99%

Transcription Factor Ets-2 Acts as a Preinduction Repressor of Interleukin-2 (IL-2) Transcription in Naive T Helper Lymphocytes

Panagoulias

Georgakopoulos

Αγγελετοπούλου

et al. 2016

Journal of Biological Chemistry

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Edited by Joel GottesfeldIL-2 is the first cytokine produced when naive T helper (Th) cells are activated and differentiate into dividing pre-Th0 proliferating precursors. IL-2 expression is blocked in naive, but not activated or memory, Th cells by the transcription factor Ets-2 that binds to the antigen receptor response element (ARRE)-2 of the proximal IL-2 promoter. Ets-2 acts as an independent preinduction repressor in naive Th cells and does not interact physically with the transcription factor NFAT (nuclear factor of activated T-cells) that binds to the ARRE-2 in activated Th cells. In naive Th cells, Ets-2 mRNA expression, Ets-2 protein levels, and Ets-2 binding to ARRE-2 decrease upon cell activation followed by the concomitant expression of IL-2. Cyclosporine A stabilizes Ets-2 mRNA and protein when the cells are activated. Ets-2 silences directly constitutive or induced IL-2 expression through the ARRE-2. Conversely, Ets-2 silencing allows for constitutive IL-2 expression in unstimulated cells. Ets-2 binding to ARRE-2 in chromatin is stronger in naive compared with activated or memory Th cells; in the latter, Ets-2 participates in a change of the IL-2 promoter architecture, possibly to facilitate a quick response when the cells re-encounter antigen. We propose that Ets-2 expression and protein binding to the ARRE-2 of the IL-2 promoter are part of a strictly regulated process that results in a physiological transition of naive Th cells to Th0 cells upon antigenic stimulation. Malfunction of such a repression mechanism at the molecular level could lead to a disturbance of later events in Th cell plasticity, leading to autoimmune diseases or other pathological conditions.

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Proteins of the ETS family with transcriptional repressor activity

Cited by 135 publications

References 106 publications

Ets-2 Repressor Factor (ERF) mediates repression of the human cytomegalovirus major immediate-early promoter in undifferentiated non-permissive cells

Ets-2 Repressor Factor (ERF) mediates repression of the human cytomegalovirus major immediate-early promoter in undifferentiated non-permissive cells

Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling

Transcription Factor Ets-2 Acts as a Preinduction Repressor of Interleukin-2 (IL-2) Transcription in Naive T Helper Lymphocytes

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