The ETS-domain transcription factor family

doi:10.1016/S1357-2725(97)00086-1

The International Journal of Biochemistry & Cell Biology

Volume 29, Issue 12, December 1997, Pages 1371-1387

https://doi.org/10.1016/S1357-2725(97)00086-1 Get rights and content

Abstract

During recent years, several significant discoveries have been made concerning the function of ETS-domain transcription factors. This family of transcription factors was originally defined on the basis of the conserved primary sequence of their DNA-binding domains. The ETS DNA-binding domain is also conserved at the structural level and is a divergent member of the winged helix-turn-helix superfamily of DNA binding proteins. This sequence conservation is reflected by their overlapping DNA-binding specificities based on the central GGAA/T motif. In addition to DNA-protein interactions, protein-protein interactions with partner proteins often play major roles in targeting ETS-domain proteins to specific promoters. Several such partner proteins have been identified. ETS-domain proteins function as either transcriptional activators or repressors and their activities are often regulated by signal transduction pathways, including the MAP kinase pathways. Specific links between such pathways and ETSdomain proteins have been established in several different experimental systems. ETS-domain transcription factors regulate a diverse array of biological functions including mammalian haematopoiesis and Drosophila eye development. In vertebrates, many ETS-domain proteins regulate embryonic and adult haematopoiesis. Deregulation of ETS-domain protein activity often leads to tumorigenesis. Future work will uncover further details of how these transcription factors work at the molecular level to regulate specific biological processes.

References (105)

A.G. Bassuk et al.
A direct physical association between ETS and AP-1 transcription factors in normal human T cells
Immunity
(1995)
J.N. Davis et al.
Cloning and expression of the murine Elf-1 cDNA
Gene
(1996)
P. Dhordain et al.
Mesodermal expression of the chicken erg gene associated with precartilaginous condensation and cartilage differentiation
Mech. Dev.
(1995)
H. Gille et al.
Activation of ternary complex factor Elk-1 by stress-activated protein kinases
Curr. Biol.
(1995)
D. Grevin et al.
Structure and organisation of the mouse elkl gene
Gene
(1996)
R. Janknecht et al.
Gene regulation by Ets proteins
-Biochim. Biophvs. Acta
(1993)
V. Laudet et al.
Evolution of the ets gene family
Biochem. Biophvs. Res. Commun.
(1993)
F. Moreau-Gachelin
Spi-IiPU.I: an oncogene of the Ets family
Biochim. Biophvs. Acta
(1994)
K. Nakae et al.
ERM, a PEA3 subfamily of Ets transcription factors, can co-operate with c-jun
J. Biol. Chem.
(1995)
E.M. O'Neill et al.
The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway
Cell
(1994)

F. Pio et al.

New insights on DNA recognition by ets proteins from the crystal structure of the PU.1 ETS domain-DNA complex

J. Biol. Chem.

(1996)

I. Rebay et al.

Yan functions as a general inhibitor of differentiation and is negatively regulated by activation of the Rasl/MAPK pathway

Cell

(1995)

J. Schneikert et al.

Androgen receptor-Ets protein interaction is a novel mechanism for steroid hormone-mediated down-modulation of matrix metalloproteinase expression

J. Biol. Chem.

(1996)

A.D. Sharrocks

ERK2/p42 MAP kinase stimulates both autonomous and SRF-dependent DNA binding by Elk-1

FEBS Lett.

(1995)

P. Shore et al.

Characterization of the Elk-1 ETS DNA-binding domain

J. Biol. Chem.

(1995)

M.H. Sieweke et al.

Maf B is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation

Cell

(1996)

M. Treier et al.

JUN cooperates with the ETS domain protein pointed to induce photoreceptor R7 fate in the Drosophila eye

Cell

(1995)

R. Treisman

Ternary complex factors: growth regulated transcriptional activators

Curr. Opin. Gen. Dev.

(1994)

R. Treisman

Regulation of transcription by MAP kinase cascades

Curr. Opin. Cell Biol.

(1996)

M.H. Werner et al.

The solution structure of the human ETSI-DNA complex reveals a novel mode of binding and true side chain intercalation

Cell

(1995)

G.J. Beitel et al.

The Caenorhabditis elegans gene lin-i encodes an ETS-domain protein and defines a branch of the vulval induction pathway

Genes Dev.

(1995)

J.C. Bories et al.

Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene

Nature

(1995)

R. Bosselut et al.

A single amino-acid substitution in the Ets domain alters core DNA binding specificity of Etsl to that of the related transcription factors Elfl and E74

Nucl. Acids Res.

(1993)

A.P. Bradford et al.

Functional interaction of c-Ets-1 and GHF-1/Pit-1 mediates Ras activation of pituitary specific gene expression: mapping of the essential c-Ets-1 domain

Mot. Cell. Biol.

(1995)

A.L. Brass et al.

Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PUA

Genes Dev.

(1996)

D. Brunner et al.

The ETS domain protein pointed-P2 is a target of MAP kinase in the sevenless signal transduction pathway

Nature

(1994)

A. Buijs et al.

Translocation (12;22) (pl3;g11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN 1 gene on 22811

Oncogene

(1995)

E. Cano et al.

Neither ERK nor JNK/SAPK MAP kinases subtypes are essential for histone H3/ HMG-14 phosphorylation or c fos and c jun induction

J. Cell Sci.

(1995)

M. Cavigelli et al.

Induction of c fos expression through JNK-mediated TCF/Elk-1 phosphorylation

EMBO J.

(1995)

P. Crepieux et al.

The Ets-family of proteins: weak modulators of gene expression in quest for transcriptional partners

Crit. Rev. Oncogen.

(1994)

B.M. Degnan et al.

The ets multigene family is conserved throughout the Metazoa

Nucl. Acids Res.

(1993)

Y. de Launoit et al.

Characterisation of the PEA3 group of ets-related transcription factors: role in breast cancer

L.W. Donaldson et al.

Solution structure of the ETSdomain from murine Ets-1: a winged helix-turn-helix motif

EMBO J.

(1996)

C.F. Eisenbeis et al.

Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator

Genes Dev.

(1995)

P. Ernst et al.

A potential role for Elf-1 in terminal transferase gene regulation

Mot. Cell. Biol.

(1996)

D. Fitzsimmons et al.

Pax-5 (BSAP) recruits Ets prolo-oncogene family proteins to form functional ternary complexes on a B-cell-specific promoter

Genes Dev.

(1996)

J.C. Fletcher et al.

The Drosophila E74 gene is required for metamorphosis and plays a role in the polytene chromosome puffing response to ecdysone

Development

(1995)

J.C. Fletcher et al.

The Drosophila E74 is required for the proper stage-and tissue-specific transcription of ecdysone regulated genes at the onset of metamorphosis

Development

(1995)

K.M. Gajewski et al.

Requirement of the ETS domain transcription factor D-ELG for egg chamber patterning and development during Drosophila oncogenesis

Oncogene

(1995)

K. Giese et al.

Assembly and function of a TCRa enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions

Genes Dev.

(1995)

H. Gille et al.

Phosphorylation-dependent formation of a quaternary complex at the c-16s SRE

Mot. Cell. Biol.

(1996)

H. Gille et al.

ERK phosphorylation potentiates Elk-I-mediated ternary complex formation and transactivation

EMBO J.

(1995)

A. Giovane et al.

Net, a new ets transcription factor that is activated by Ras

Genes Dev.

(1994)

T.R. Golub et al.

Fusion of the TEL gene on l2p13 to the AML gene on 21822 in acute lymphoblastic leukemia

T.R. Golub et al.

Oligomerisation of the ABL tyrosine kinase by the Ets protein TEL in human leukemia

Mot. Cell. Biol.

(1996)

B.J. Graves et al.

DNA binding by the ETS-domain

Nature

(1996)

C.V. Gunther et al.

Identification of ETS domain proteins in murine T-lymphocytes that interact with the Moloney murine leukemia virus enhancer

Mot. Cell. Biol.

(1994)

S.W. Hiebert et al.

The t(12;21) translocation converts AMLAB from an activator to a repressor of transcription

Mot. Cell. Biol.

(1996)

R. Janknecht

Analysis of the ERK-stimulated ETS transcription factor ER81

Mol. Cell. Biol.

(1996)

R. Janknecht et al.

SAP I a is a nuclear target of signaling cascades involving ERKs

Oncogene

(1995)

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The ETS domain transcription factor family is one of the major transcription factor superfamilies that play regulatory roles in development, cell growth, and cancer progression. Although different functions of ETS member proteins in the nervous system have been demonstrated in various studies, their role in neuronal cell differentiation and the evolutionary conservation of its target genes have not yet been extensively studied. In this study, we focused on the regulatory role of ETS transcription factors in neuronal differentiation and their functional evolution by comparative transcriptomics. In order to investigate the regulatory role of ETS transcription factors in neuronal differentiation across species, transcriptional profiles of ETS members and their target genes were investigated by comparing differentially expressed genes and gene regulatory networks, which were analyzed using human, gorilla, mouse, fruit fly and worm transcriptomics datasets. Bioinformatics approaches to examine the evolutionary conservation of ETS transcription factors during neuronal differentiation have shown that ETS member proteins regulate genes associated with neuronal differentiation, nervous system development, axon, and synaptic regulation in different organisms. This study is a comparative transcriptomic study of ETS transcription factors in terms of neuronal differentiation using a gene regulatory network inference algorithm. Overall, a comparison of gene regulation networks revealed that ETS members are indeed evolutionarily conserved in the regulation of neuronal differentiation. Nonetheless, ETS, PEA3, and ELF subfamilies were found to be relatively more active transcription factors in the transcriptional regulation of neuronal differentiation.
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E74 is a key transcription factor induced by 20E, which plays a broad role in many physiological events during insect growth and development, including vitellogenesis, organ remodeling and new tissue formation, programmed cell death and metamorphosis. However, whether it is involved in regulating insect chitin biosynthesis remains largely unclear. Here, the E74 gene was identified for the first time from Hyphantria cunea, a notorious defoliator of forestry. Thereafter, the role of HcE74 in regulating growth, development and chitin synthesis in H. cunea larvae was evaluated. Bioinformatics analysis showed that HcE74 shared the highest identity (95.53%) with E74A of Spodoptera litura, which belonged to Ets superfamily. The results of RNAi bioassay showed that the larval mortality on 6 d after HcE74 knockdown was up to 51.11 ± 6.94%. Meanwhile, a distinct developmental deformity phenotype was found when HcE74 was silenced. These results indicated that HcE74 plays an important role in the development and molting of H. cunea larvae. Moreover, HcE74 knockdown also significantly decreased the expression of four key genes related to chitin synthesis, including glucose-6-phosphate isomerase (HcG6PI), UDP-N-acetylglucosamine pyrophosphorylase (HcUAP), chitin synthetase A (HcCHSA), and chitin synthetase B (HcCHSB). As a result, the content of chitin in midgut and epidermis decreased by 0.54- and 0.08-fold, respectively. Taken together, these results demonstrated that HcE74 not only plays a critical role in the growth and molting of H. cunea larvae, but also probably participates in the transcriptional regulation of genes involved in chitin biosynthesis.
Identification of multifunctionality of the PmE74 gene and development of SNPs associated with low salt tolerance in Penaeus monodon
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Members of the E74-like factor (ELF) subfamily are involved in the immune stress process of organisms by regulating immune responses and the development of immune-related cells. PmE74 of Penaeus monodon was characterized and functionally analyzed in this study. The full length of PmE74 was 3106 bp, with a 5′-UTR of 297 bp, and a 3′-UTR of 460 bp. The ORF (Open reading frame) was 2349 bp and encoded 782 amino acids. Domain analysis showed that PmE74 contains a typical Ets domain. Multiple sequence alignment and phylogenetic tree analysis showed that PmE74 clustered with Litopenaeus vannamei E74 and displayed significant similarity (98.98%). PmE74 was expressed in all tissues tested in P. monodon, with the highest levels of expression observed in the testis, intestine, and epidermis. Different pathogen stimulation studies have revealed that PmE74 expression varies in response to different pathogen stimuli. A 96-h acute low salt stress study revealed that PmE74 in the hepatopancreas was upregulated and downregulated in the salinity 17 group and considerably downregulated in the salinity 3 group, whereas PmE74 in gill tissue was considerably downregulated in both groups. Further, by knocking down PmE74 and learning the trends of its linkage genes PmAQP1, PmNKA, PmE75, PmFtz-f1, PmEcR, and PmRXR in response to low salt stress, it was further indicated that PmE74 could have a vital role in the regulation of low salt stress. The SNP test revealed that PmE74-In1-53 was significantly associated with low salt tolerance traits in P. monodon (P < 0.05). The findings of this study can aid in the advancement of molecular marker-assisted breeding in P. monodon, as well as provide fundamental data and methodologies for further investigation of its low salt tolerance strains in P. monodon.
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Citation Excerpt :
This result indicated that up-regulated miR-7134-5p targeting NFATC4 may be beneficial to resisting C. perfringens type C. ELK1 is a transcription factor of a member of the ternary complex factor (TCF) subfamily of the ETS family [39]. Studies showed that ELK1 was participated in virus-induced diseases.
Clostridium perfringens (C. perfringens) type C is one of major pathogenic causing diarrhea and other intestinal inflammatory diseases in piglets, which seriously affects the healthy development of the swine industries. Studies have found that miRNAs play important roles in regulating piglet diarrhea challenged by pathogenic E. coli and Salmonella. However, little is known miRNAs in the ileum of diarrheic piglets caused by C. perfringens type C. Therefore, we studied the expression profiles of the ileum miRNAs of 7-day-old piglets infected with C. perfringens type C using small RNA-Seq, including control (IC), susceptible (IS) and resistant (IR) groups. As a result, 53 differentially expressed miRNAs were found. KEGG pathway analysis for target genes revealed that these miRNAs were involved in ErbB signaling pathway, MAPK signaling pathway, Jak-STAT signaling pathway and Wnt signaling pathway. The expression correlation analysis between miRNAs and target genes revealed that the expression of miR-7134-5p had negative correlation with target NFATC4, miR-500 had negative correlation with target ELK1, HSPA2 and IL7R, and miR-92b-3p had negative correlation with target CLCF1 in ileum of IR vs IS group, suggesting that miR-7134-5p targeting to NFATC4, miR-500 targeting to ELK1, HSPA2 and IL7R, and miR-92b-3p targeting to CLCF1 were probably involved in piglet resisting C. perfringens type C. The results will provide value resources for better understanding of the genetic basis of C. perfringens type C resistance in piglet and lays a new foundation for identifying novel markers of C. perfringens type C resistance.
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MicroRNAs (miRNAs) play important roles in tumorigenesis and tumor progression. In this study, we investigated the role of miR-320a-3p in non-small cell lung cancer (NSCLC). Expressions of miR-320a-3p were firstly determined in 80 NSCLC patients' cancer tissues and adjacent normal lung tissues by qRT-PCR. Then MTT assay, cell migration and invasion assays were performed in vitro. Potential binding sites on target gene of miR-320a-3p were predicted and luciferase reporter assay was used to identify the potential binding sites. Tumorigenesis assay were performed in nude mice by injecting A549 cells which stably express miR-320a-3p. Results indicated that high expression of miR-320a-3p suppresses cell proliferation, migration and invasion through the inactivation of PI3K/Akt signaling pathway in NSCLC cells. Smaller tumor size and lighter weight were also found in nude mice which had miR-320a-3p higher expressed. Furthermore, data from luciferase reporter assay proved the direct binding of miR-320a-3p on the 3′UTR region of ELF3 mRNA, this could further decrease ELF3 expression transcriptionally. We provided evidence that miR-320a-3p might work as a tumor suppressor in NSCLC both in vivo and in vitro.
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Citation Excerpt :
The ETS1 gene was first identified as the cellular precursor of the viral Ets1 oncogene, which induces a mixed erythroleukemia in chickens, in association with v-Myb [30]. ETS1 belongs to a large family of transcription factors characterized by a unique DNA-binding ETS domain [31]. ETS1 has been implicated in granulocytic [18] and erythro/megakaryocytic [32] lineage differentiation and therefore could support the massive myeloid amplification observed in dysregulated CML hematopoiesis.
The BCR-ABL oncogene, the hallmark of chronic myeloid leukemia (CML), has been shown to activate several signaling pathways in leukemic cells. The natural history of this disease has been radically modified by tyrosine kinase inhibitors (TKIs). However, resistance to several lines of TKI therapies and progression to blast crisis (BC) remain significant concerns. To identify novel signaling pathways induced by BCR-ABL, we performed a transcriptome analysis in a BCR-ABL-expressing UT-7 cell line. More than 2000 genes differentially expressed between BCR-ABL-expressing and parental UT-7 cells were identified and ETS1 was found to be the most upregulated. ETS1 protein expression was also shown to be highly increased in UT-7 cells expressing BCR-ABL either constitutively or under the control of TET-inducible promoters. ETS1 expression is tyrosine-kinase dependent because it was reduced by TKIs. A significant increase of ETS1 messenger RNA (mRNA) expression was observed in blood cells from CML patients at diagnosis compared with healthy controls. Integration of publicly available chromatin immunoprecipitation sequencing and transcriptomic data with our results allowed us to identify potential ETS1 targets, some of which are involved in the progression of CML. The messenger RNA expression of two of these genes (DNM3 and LIMS1) was found to be associated with the absence of major cytogenetic response after 1 year of imatinib therapy. The present work demonstrates for the first time the involvement of the ETS1 transcriptional program in the experimental UT-7 model and a large cohort of CML patients.

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ReviewThe ETS-domain transcription factor family

Abstract

Immunity

Gene

Mech. Dev.

Curr. Biol.

Gene

-Biochim. Biophvs. Acta

Biochem. Biophvs. Res. Commun.

Biochim. Biophvs. Acta

J. Biol. Chem.

Cell

J. Biol. Chem.

Cell

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Cell

Cell

Curr. Opin. Gen. Dev.

Curr. Opin. Cell Biol.

Cell

The Caenorhabditis elegans gene lin-i encodes an ETS-domain protein and defines a branch of the vulval induction pathway

Genes Dev.

Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene

Nature

A single amino-acid substitution in the Ets domain alters core DNA binding specificity of Etsl to that of the related transcription factors Elfl and E74

Nucl. Acids Res.

Functional interaction of c-Ets-1 and GHF-1/Pit-1 mediates Ras activation of pituitary specific gene expression: mapping of the essential c-Ets-1 domain

Mot. Cell. Biol.

Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PUA

Genes Dev.

The ETS domain protein pointed-P2 is a target of MAP kinase in the sevenless signal transduction pathway

Nature

Translocation (12;22) (pl3;g11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN 1 gene on 22811

Oncogene

Neither ERK nor JNK/SAPK MAP kinases subtypes are essential for histone H3/ HMG-14 phosphorylation or c fos and c jun induction

J. Cell Sci.

Induction of c fos expression through JNK-mediated TCF/Elk-1 phosphorylation

EMBO J.

The Ets-family of proteins: weak modulators of gene expression in quest for transcriptional partners

Crit. Rev. Oncogen.

The ets multigene family is conserved throughout the Metazoa

Nucl. Acids Res.

Characterisation of the PEA3 group of ets-related transcription factors: role in breast cancer

Solution structure of the ETSdomain from murine Ets-1: a winged helix-turn-helix motif

EMBO J.

Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator

Genes Dev.

A potential role for Elf-1 in terminal transferase gene regulation

Mot. Cell. Biol.

Pax-5 (BSAP) recruits Ets prolo-oncogene family proteins to form functional ternary complexes on a B-cell-specific promoter

Genes Dev.

The Drosophila E74 gene is required for metamorphosis and plays a role in the polytene chromosome puffing response to ecdysone

Development

The Drosophila E74 is required for the proper stage-and tissue-specific transcription of ecdysone regulated genes at the onset of metamorphosis

Development

Requirement of the ETS domain transcription factor D-ELG for egg chamber patterning and development during Drosophila oncogenesis

Oncogene

Assembly and function of a TCRa enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions

Genes Dev.

Phosphorylation-dependent formation of a quaternary complex at the c-16s SRE

Mot. Cell. Biol.

ERK phosphorylation potentiates Elk-I-mediated ternary complex formation and transactivation

EMBO J.

Net, a new ets transcription factor that is activated by Ras

Genes Dev.

Fusion of the TEL gene on l2p13 to the AML gene on 21822 in acute lymphoblastic leukemia

Oligomerisation of the ABL tyrosine kinase by the Ets protein TEL in human leukemia

Mot. Cell. Biol.

DNA binding by the ETS-domain

Nature

Identification of ETS domain proteins in murine T-lymphocytes that interact with the Moloney murine leukemia virus enhancer

Mot. Cell. Biol.

The t(12;21) translocation converts AMLAB from an activator to a repressor of transcription

Mot. Cell. Biol.

Analysis of the ERK-stimulated ETS transcription factor ER81

Mol. Cell. Biol.

SAP I a is a nuclear target of signaling cascades involving ERKs

Oncogene

Review
The ETS-domain transcription factor family