ETS transcription factor family

Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary
PDB	1awc , 1bc7 , 1bc8 , 1dux , 1fli , 1gvj , 1hbx , 1k6o , 1k78 , 1k79 , 1k7a , 1md0 , 1mdm , 1pue , 1r36 , 1wwx , 1yo5 , 2nny , 2stt , 2stw

Ets-domain
Ets-domain
	Structure of Ets-1 DNA binding autoinhibition.
Identifiers
Symbol	Ets
Pfam	PF00178
Pfam clan	CL0123
InterPro	IPR000418
SMART	SM00413
PROSITE	PDOC00374
SCOP2	1r36 / SCOPe / SUPFAM
Pfam
Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary
PDB	1awc , 1bc7 , 1bc8 , 1dux , 1fli , 1gvj , 1hbx , 1k6o , 1k78 , 1k79 , 1k7a , 1md0 , 1mdm , 1pue , 1r36 , 1wwx , 1yo5 , 2nny , 2stt , 2stw

Last updated August 10, 2022

In the field of molecular biology, the ETS (E26 transformation-specific^[2] or E-twenty-six. (Erythroblast Transformation Specific)^[3]) family is one of the largest families of transcription factors and is unique to animals. There are 29 genes in humans, 28 in the mouse, 10 in Caenorhabditis elegans and 9 in Drosophila. The founding member of this family was identified as a gene transduced by the leukemia virus, E26. The members of the family have been implicated in the development of different tissues as well as cancer progression.

Subfamilies

The ETS (Erythroblast Transformation Specific)family is divided into 12 subfamilies, which are listed below:^[4]

Subfamily	Mammalian family members	Invertebrate orthologs
ELF	ELF1, ELF2 (NERF), ELF4 (MEF)
ELG	GABPα	ELG
ERG	ERG, FLI1, FEV
ERF	ERF (PE2), ETV3 (PE1)
ESE	ELF3 (ESE1/ESX), ELF5 (ESE2), ESE3 (EHF)
ETS	ETS1, ETS2	POINTED
PDEF	SPDEF (PDEF/PSE)
PEA3	ETV4 (PEA3/E1AF), ETV5 (ERM), ETV1 (ER81)
ER71	ETV2 (ER71)
SPI	SPI1 (PU.1), SPIB, SPIC
TCF	ELK1, ELK4 (SAP1), ELK3 (NET/SAP2)	LIN
TEL	ETV6 (TEL), ETV7 (TEL2)	YAN

Structure

All ETS (Erythroblast Transformation Specific) family members are identified through a highly conserved DNA binding domain, the ETS domain, which is a winged helix-turn-helix structure that binds to DNA sites with a central GGA(A/T) DNA sequence. As well as DNA-binding functions, evidence suggests that the ETS domain is also involved in protein-protein interactions. There is limited similarity outside the ETS DNA binding domain.

Other domains are also present and vary from ETS member to ETS member, including the Pointed domain, a subclass of the SAM domain family.

Function

The ETS family is present throughout the body and is involved in a wide variety of functions including the regulation of cellular differentiation, cell cycle control, cell migration, cell proliferation, apoptosis (programmed cell death) and angiogenesis.

Multiple ETS factors have been found to be associated with cancer, such as through gene fusion. For example, the ERG ETS transcription factor is fused to the EWS gene, resulting in a condition called Ewing's sarcoma.^[5] The fusion of TEL to the JAK2 protein results in early pre-B acute lymphoid leukaemia.^[6] ERG and ETV1 are known gene fusions found in prostate cancer.^[7]

In addition, ETS factors, e.g. the vertebrate Etv1 and the invertebrate Ast-1, have been shown to be important players in the specification and differentiation of dopaminergic neurons in both C. elegans and olfactory bulbs of mice.^[8]

Mode of action

Amongst members of the ETS family, there is extensive conservation in the DNA-binding ETS domain and, therefore, a lot of redundancy in DNA binding. It is thought that interactions with other proteins (eg: Modulator of the activity of Ets called Mae) is one way in which specific binding to DNA is achieved. Transcription factor Ets are a site of signalling convergence.^[9] ETS factors act as transcriptional repressors, transcriptional activators, or both.^[10]

Related Research Articles

Ewing sarcoma is a type of cancer that forms in bone or soft tissue. Symptoms may include swelling and pain at the site of the tumor, fever, and a bone fracture. The most common areas where it begins are the legs, pelvis, and chest wall. In about 25% of cases, the cancer has already spread to other parts of the body at the time of diagnosis. Complications may include a pleural effusion or paraplegia.

ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.

Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene. The protein encoded by this gene belongs to the ETS family of transcription factors.

Friend leukemia integration 1 transcription factor (FLI1), also known as transcription factor ERGB, is a protein that in humans is encoded by the FLI1 gene, which is a proto-oncogene.

Cyclic AMP-dependent transcription factor ATF-1 is a protein that in humans is encoded by the ATF1 gene.

Protein C-ETS2 is a protein that in humans is encoded by the ETS2 gene. The protein encoded by this gene belongs to the ETS family of transcription factors.

ETS translocation variant 4 (ETV4), also known as polyoma enhancer activator 3 (PEA3), is a member of the PEA3 subfamily of Ets transcription factors.

LIM domain only 2, also known as LMO2, RBTNL1, RBTN2, RHOM2, LIM Domain Only Protein 2, TTG2, and T-Cell Translocation Protein 2, is a protein which in humans is encoded by the LMO2 gene.

Transcription factor PU.1 is a protein that in humans is encoded by the SPI1 gene.

RNA-binding protein EWS is a protein that in humans is encoded by the EWSR1 gene on human chromosome 22, specifically 22q12.2. It is one of 3 proteins in the FET protein family. The q22.2 region of chromosome 22 encodes the N-terminal transactivation domain of the EWS protein and that region may become joined to one of several other chromosomes which encode various transcription factors, see and the FET protein family. The expression of a chimeric protein with the EWS transactivation domain fused to the DNA binding region of a transcription factor generates a powerful oncogenic protein causing Ewing sarcoma and other members of the Ewing family of tumors. These translocations can occur due to chromoplexy, a burst of complex chromosomal rearrangements seen in cancer cells. The normal EWS gene encodes an RNA binding protein closely related to FUS (gene) and TAF15, all of which have been associated to amyotrophic lateral sclerosis.

ERG is an oncogene. ERG is a member of the ETS family of transcription factors. The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis.

RNA-binding protein FUS/TLS, also known as heterogeneous nuclear ribonucleoprotein P2 is a protein that in humans is encoded by the FUS gene.

ETS translocation variant 1 is a protein that in humans is encoded by the ETV1 gene.

ETS domain-containing protein Elk-4 is a protein that in humans is encoded by the ELK4 gene.

ETS domain-containing protein Elk-3 is a protein that in humans is encoded by the ELK3 gene.

E74-like factor 5 , is a gene found in both mice and humans. In humans it is also called ESE2.

Transcription factor ETV7 is a protein that in humans is encoded by the ETV7 gene.

SAP1A is one of a family of proteins that contains a unique DNA binding domain termed the ETS domain.

EWS/FLI1 is an oncogenic protein that is pathognomonic for Ewing sarcoma. It is found in approximately 90% of all Ewing sarcoma tumors with the remaining 10% of fusions substituting one fusion partner with a closely related family member.

The FET protein family the EWSR1 protein encoded by the EWSR1 gene located at band 12.2 of the long arm of chromosome 22; 2) the FUS protein encoded by the FUS gene located at band 16 on the short arm of chromosome 16; and 3) the TAF15 protein encoded by the TAF15 gene located at band 12 on the long arm of chromosome 7 The FET in this protein family's name derives form the first letters of FUS, EWSR1, and TAF15.

References

↑ Lee GM, Donaldson LW, Pufall MA, et al. (February 2005). "The structural and dynamic basis of Ets-1 DNA binding autoinhibition". J. Biol. Chem. 280 (8): 7088–99. doi: 10.1074/jbc.M410722200 . PMID 15591056.
↑ Nunn, M. F.; Seeburg, P. H.; Moscovici, C.; Duesberg, P. H. (1983). "Tripartite structure of the avian erythroblastosis virus E26 transforming gene". Nature. 306 (5941): 391–395. Bibcode:1983Natur.306..391N. doi:10.1038/306391a0. PMID 6316155. S2CID 4302399.
↑ Leprince, D.; Gegonne, A.; Coll, J.; De Taisne, C.; Schneeberger, A.; Lagrou, C.; Stehelin, D. (1983). "A putative second cell-derived oncogene of the avian leukaemia retrovirus E26". Nature. 306 (5941): 395–397. Bibcode:1983Natur.306..395L. doi:10.1038/306395a0. PMID 6316156. S2CID 4318034.
↑ Gutierrez-Hartman A, Duval DL, Bradford AP (2007). "ETS transcription factors in endocrine systems". Trends Endocrinol Metab. 18 (4): 150–8. doi:10.1016/j.tem.2007.03.002. PMID 17387021. S2CID 24617218.
↑ Ida K, Kobayashi S, Taki T, Hanada R, Bessho F, Yamamori S, Sugimoto T, Ohki M, Hayashi Y (1995). "EWS-FLI-1 and EWS-ERG chimeric mRNAs in Ewing's sarcoma and primitive neuroectodermal tumor". Int J Cancer. 63 (4): 500–4. doi:10.1002/ijc.2910630407. PMID 7591257. S2CID 24841690.
↑ Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, Monpoux F, Van Rompaey L, Baens M, Van den Berghe H, Marynen P (1997). "Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia". Blood. 90 (7): 2535–40. doi: 10.1182/blood.V90.7.2535 . PMID 9326218.
↑ Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM (October 2005). "Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer". Science . 310 (5748): 644–8. Bibcode:2005Sci...310..644T. doi:10.1126/science.1117679. PMID 16254181. S2CID 85788789.
↑ Flames N, Hobert O (2009). "Gene regulatory logic of dopaminergic neuron differentiation". Nature. 458 (7240): 885–890. doi:10.1038/nature07929. PMC 2671564 . PMID 19287374.
↑ Verger A, Duterque-Coquillaud M (2002). "When Ets transcription factors meet their partners". BioEssays. 24 (4): 362–70. doi:10.1002/bies.10068. PMID 11948622.
↑ Sharrocks AD (2001). "The ETS-domain transcription factor family". Nat Rev Mol Cell Biol. 2 (11): 827–37. doi:10.1038/35099076. PMID 11715049. S2CID 5407789.