The International Journal of Biochemistry & Cell Biology
ReviewThe Ets family contains transcriptional activators and repressors involved in angiogenesis
Section snippets
A short presentation of Ets family members, their domains and their partners
The proto-oncogene ets1 is the cellular progenitor of v-ets, a viral oncogene found in the genome of the E26 acute leukaemia retrovirus [1], [2]. Ets-1 is the founder of a growing family of transcription factors which includes over 50 members characterised by a conserved DNA-binding domain. Some proteins of the family, such as Ets1, Ets2, Erg, Tel and Fli1 harbour another conserved region named the pointed domain, located in their N-terminal part. The origin of the Ets family seems extremely
Expression patterns of Ets family members during normal and pathological development
A first step towards understanding the biological roles of Ets1 has been the identification of cells in which Ets1 might act. A predominant expression of ets1 has been initially detected in the lymphoid organs of neonatal and adult mice, in discrete T and B cell developmental stages, in lymphoid precursors, in immature NK-like cells and myeloid hematopoietic cells [20].
In situ hybridisation analyses carried out during embryonic development revealed a more widespread expression in a variety of
Control of the expression and activity of Ets members
The expression of Ets1 transcripts is associated in vivo with the activation of endothelial cells and the induction of angiogenesis. In vitro, Ets1 is expressed by proliferating [28] and migrating [27] endothelial cells but not after these cells have reached confluence [28]. In addition, Ets1 is hyper-phosphorylated during early mitosis in T-cell lines, suggesting a regulation of its activity during cell proliferation [42]. Expression of Ets1 in endothelial cells is increased in response to
The involvement of Ets1 in the stress response
The GGAA/T core sequence recognised by Ets factors [53] is present in the sequence recognised by heat-shock factors, and similarities have been found between the DNA-binding domains of heat-shock and of Ets factors [54]. This, together with the regulation of Ets factors activity by stress-kinases, suggests that Ets members are involved in the cell response to stress. The vascular endothelium is one of the prime targets for oxidative stress in a variety of inflammatory conditions, possibly
From promoters studies to the identification of target genes
The role of Ets family members during angiogenesis has been partially addressed by the dissection of the cis-acting elements involved in the regulation of endothelial specific genes. An alternative approach has been to over-express or down-regulate these factors in endothelial cells and to analyse variations in the expression levels of endogenous genes. These methods have allowed the identification of several endothelial specific Ets target genes.
What is the role of Ets members in endothelial cells? Insights from in vitro studies
Ets factors are able to transactivate the genes encoding matrix degrading proteases, cell-to-matrix and cell-to-cell adhesion molecules such as integrins, cadherins and intercellular adhesion molecules. Several studies on the effects of various Ets mutants have indicated that Ets factors could be involved in regulating cell adhesion, spreading and migration. Expression of the DNA binding domains of PU1, Ets1 and Ets2 reverts Ras-transformed 3T3 cells, which become larger and flatter with an
In vivo studies and the proof by KO
The search for Ets target genes provided clues for understanding the molecular mechanisms by which these factors might act. In parallel, various strategies have been carried out to understand the role of each Ets family members in the progression of physiological processes.
Conclusion and directions for future research
In vitro bioassays and experimental tumour models indicate that the angiogenic switch is governed by a balance between inhibitors (thrombospondins, angiostatin or endostatin) and activators (FGF-2, VEGF). The description of the expression patterns of Ets family members and functional studies suggest that these transcription factors may control angiogenesis both positively and negatively (Fig. 3).
The Ets family contains both transcriptional activators and inhibitors. Specific probes and
Acknowledgements
Work in the laboratory was funded by the Conseil Régional du Nord Pas de Calais and the European Regional Development Fund, the Association pour la Recherche sur le Cancer, Ligue Nationale contre le Cancer, Fondation pour la Recherche Médicale, Groupement des Entreprises Françaises dans la Lutte contre le Cancer. FS is ‘Chargé de Recherche de l'Institut National de la Santé et de la Recherche Médicale’. EL is supported by a fellowship from the'Ministère de l'Education Nationale, de la Recherche
References (116)
- et al.
Calcium-induced phosphorylation of ETS1 inhibits its specific DNA binding activity
J. Biol. Chem.
(1994) - et al.
The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner
J. Biol. Chem.
(1997) - et al.
MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation
Cell
(1996) - et al.
p300/cAMP-responsive element-binding protein interactions with ets-1 and ets-2 in the transcriptional activation of the human stromelysin promoter
J. Biol. Chem.
(1999) - et al.
TEL is a sequence-specific transcriptional repressor
J. Biol. Chem.
(1999) - et al.
The ets family member Tel binds to the Fli-l oncoprotein and inhibits its transcriptional activity
J. Biol. Chem.
(1998) - et al.
The c-ets 1 protooncogene is expressed in human trophoblast during the first trimester of pregnancy
Early Hum. Dev.
(1997) - et al.
Expression of the c-etsl gene in the hypothalamus and pituitary during rat development
Brain Res. Dev. Brain Res.
(1996) - et al.
Expression of Ets-1 transcription factor in relation to angiogenesis in the healing process of gastric ulcer
Biochem. Biophys. Res. Commun.
(1998) - et al.
Mesodermal expression of the chicken erg gene associated with precartilaginous condensation and cartilage differentiation
Mec. Dev.
(1995)
Insights into early vasculogenesis revealed by expression of the ETSdomain transcription factor Fli-1 in wild-type and mutant zebrafish embryos
Mech. Dev.
Requirement of a GT box (Sp1 site) and two Ets binding sites for vascular endothelial cadherin gene transcription
J. Biol. Chem.
Calcium-induced phosphorylation of Etsl inhibits its specific DNA binding activity
J. Biol. Chem.
Regulation of transcription by MAP kinase cascades
Curr. Opin. Cell. Biol.
Small mechanical strains selectively suppress matrix metalloproteinase-1 expression by human vascular smooth muscle cells
J. Biol. Chem.
Common sequence and structural features in the heat-shock factor and Ets families of DNA-binding domains
TIBS
H2O2 and tumor necrosis factor-alpha activate intercellular adhesion molecule 1 (ICAM-1) gene transcription through distinct cis-regulatory elements within the ICAM-1 promoter
J. Biol. Chem.
Endothelial-specific gene expression directed by the tie gene promoter in vivo
Blood
Molecular cloning and expression of murine vascular endothelial-cadherin in early stage development of cardiovascular system
Blood
Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis
Cell
The vascular endothelial-cadherin promoter directs endothelial-specific expression in transgenic mice
Blood
A novel promoter for vascular endothelial growth factor receptor (fit-1) that confers endothelial-specific gene expression
J. Biol. Chem.
A cyclic AMP response element and an ETS motif are involved in the transcriptional regulation of fit-1 tyrosine kinase (VEGF receptor 1) gene
J. Biol. Chem.
Identification of vascular endothelial growth factor (VEGF) receptor-2 (Flk-1) promoter/enhancer sequences sufficient for angioblast and endothelial cell-specific transcription in transgenic mice
Blood
The Ets-1 transcription factor is required for the development of natural killer cells in mice
Immunity
Thymidine phosphorylase (platelet-derived endothelial cell growth factor), microvessel density and clinical outcome in hepatocellular carcinoma [In Process Citation]
J. Hepatol.
Novel cis-acting elements in the human platelet-derived growth factor B-chain core promoter that mediate gene expression in cultured vascular endothelial cells
J. Biol. Chem.
Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1
Blood
A putative second cell-derived oncogene of the avian leukaemia retrovirus E26
Nature
Tripartite structure of the avian erythroblastosis virus E26 transforming gene
Nature
Molecular phylogeny of the ETS gene family
Oncogene
The ETS family of transcriptional regulators
Modulation of transcription factor Ets-1 DNA binding: DNA-induced unfolding of an alpha helix
Science
Auto-inhibition of Ets-1 is counteracted by DNA binding cooperativity with core-binding factor alpha2
Mol. Cell. Biol.
Phosphorylation represses Ets-1 DNA binding by reinforcing autoinhibition
Genes Dev.
Isoforms of the human ets-1 protein: generation by alternative splicing and differential phosphorylation
Oncogene
ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation
EMBO J.
The cets proto-oncogenes encode transcription factors that cooperate with c-fos and c-jun for transcriptional activation
Nature
Erg, an Ets-family member, differentially regulates human collagenasel (MMP1) and stromelysini (MMP3) gene expression by physically interacting with the Fos/Jun complex
Oncogene
EAP1/Daxx interacts with ETS1 and represses transcriptional activation of ETS 1 target genes
Oncogene
A role for CREB binding protein and p300 transcriptional coactivators in Ets-1 transactivation functions
Mol. Cell. Biol.
Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage
Development
Expression of C-ETS1 in early chick embryo mesoderm: relationship to the hemangioblastic lineage
Cell Adhes. Commun.
p54c-ets-1 and p68c-ets1, the two transcription factors encoded by the c-ets-1 locus, are differentially expressed during the development of the chick embryo
Oncogene
Involvement of the proto-oncogene c-ets 1 and the urokinase plasminogen activator during mouse implantation and placentation
Int. J. Dev. Biol.
Complementary patterns of expression of c-etsl, c-myb and c-myc in the blood-forming system of the chick embryo
Development
Induction of Ets-1 in endothelial cells during reendothelialization after denuding injury
J. Cell. Physiol.
The c-ets 1 proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularisation and other forms of angiogenesis in man
Am. J. Path.
Expression of the Ets-l transcription factor in human astrocytomas is associated with Fms-like tyrosine kinase-1 (Flt-1)/vascular endothelial growth factor receptor-1 synthesis and neoangiogenesis
Cancer Res.
The Etsl transcription factor is widely expressed during murine embryo development and is associated with mesodermal cells involved in morphogenic processes such as organ formation
Proc. Natl. Acad. Sci. USA
Cited by (136)
Neurooncogenesis in the Development of Neuroectodermal Cancers
2021, The Molecular Immunology of Neurological DiseasesVegf signaling promotes vascular endothelial differentiation by modulating etv2 expression
2017, Developmental BiologyProteasomal degradation of the EWS-FLI1 fusion protein is regulated by a single lysine residue
2016, Journal of Biological ChemistryRegulation of endothelial homeostasis, vascular development and angiogenesis by the transcription factor ERG
2016, Vascular Pharmacology