ETS transcription factor family

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Ets-domain
PDB 1r36 EBI.jpg
Structure of Ets-1 DNA binding autoinhibition. [1]
Identifiers
SymbolEts
Pfam PF00178
Pfam clan CL0123
InterPro IPR000418
SMART SM00413
PROSITE PDOC00374
SCOP2 1r36 / SCOPe / SUPFAM
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

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 28 genes in humans [4] , 27 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.

Contents

Subfamilies

The ETS (Erythroblast Transformation Specific)family is divided into 12 subfamilies, which are listed below: [5]

SubfamilyMammalian family membersInvertebrate orthologs
ELF ELF1, ELF2 (NERF), ELF4 (MEF)
ELG GABPα ELG
ERG ERG, FLI1, FEV
ERF ERF (PE2), ETV3 (PE1), ETV3L
ESE ELF3 (ESE1/ESX), ELF5 (ESE2), ESE3 (EHF)
ETS ETS1, ETS2 POINTED
PDEF SPDEF (PDEF/PSE)
PEA3 ETV4 (PEA3/E1AF), ETV5 (ERM), ETV1 (ER81)
ER71ETV2 (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. [6] The fusion of TEL to the JAK2 protein results in early pre-B acute lymphoid leukaemia. [7] ERG and ETV1 are known gene fusions found in prostate cancer. [8]

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. [9]

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. [10] ETS factors act as transcriptional repressors, transcriptional activators, or both. [11]

Related Research Articles

<span class="mw-page-title-main">Ewing sarcoma</span> Type of cancer

Ewing sarcoma is a type of pediatric 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.

<span class="mw-page-title-main">ETV6</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">ETS1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">ELK1</span> Protein-coding gene in humans

ETS Like-1 protein Elk-1 is a protein that in humans is encoded by the ELK1. Elk-1 functions as a transcription activator. It is classified as a ternary complex factor (TCF), a subclass of the ETS family, which is characterized by a common protein domain that regulates DNA binding to target sequences. Elk1 plays important roles in various contexts, including long-term memory formation, drug addiction, Alzheimer's disease, Down syndrome, breast cancer, and depression.

<span class="mw-page-title-main">HOXA9</span> Protein-coding gene in humans

Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.

<span class="mw-page-title-main">FLI1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">ATF1</span> Protein-coding gene in humans

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

<span class="mw-page-title-main">ETS2</span> Protein-coding gene in humans

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. It has been found to play a key role in the development of inflammatory bowel disease.

<span class="mw-page-title-main">ETV4</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">SPI1</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">RNA-binding protein EWS</span> Human protein and coding 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.

<i>ERG</i> (gene) Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">RNA-binding protein FUS</span> Human protein and coding gene

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

<span class="mw-page-title-main">ETV1</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">ELK4</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">ELK3</span> Protein-coding gene in humans

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

<span class="mw-page-title-main">ELF5</span> Protein-coding gene

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

<span class="mw-page-title-main">PATZ1</span> Protein-coding gene in the species Homo sapiens

POZ-, AT hook-, and zinc finger-containing protein 1 is a protein that in humans is encoded by the PATZ1 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.

References

  1. 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.
  2. 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.
  3. 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.
  4. Sizemore, Gina M.; Pitarresi, Jason R.; Balakrishnan, Subhasree; Ostrowski, Michael C. (June 2017). "The ETS family of oncogenic transcription factors in solid tumours". Nature Reviews Cancer. 17 (6): 337–351. doi:10.1038/nrc.2017.20. ISSN   1474-1768. PMID   28450705.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.

Further reading