ETS transcription factor family explained

Symbol:Ets
Ets-domain
Pfam:PF00178
Pfam Clan:CL0123
Interpro:IPR000418
Smart:SM00413
Prosite:PDOC00374
Scop:1r36
Pdb:,,,,,,,,,,,,,,,,,,,

In the field of molecular biology, the ETS (E26 transformation-specific[1] or E-twenty-six. (Erythroblast Transformation Specific)[2]) family is one of the largest families of transcription factors and is unique to animals. There are 28 genes in humans[3], 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.

Subfamilies

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

SubfamilyMammalian family membersInvertebrate orthologs
ELF ELF1, ELF2 (NERF), ELF4 (MEF)
ELGELG
ERGERG, FLI1, FEV
ERFERF (PE2), ETV3 (PE1), ETV3L
ESEELF3 (ESE1/ESX), ELF5 (ESE2), ESE3 (EHF)
ETSETS1, ETS2POINTED
PDEFSPDEF (PDEF/PSE)
PEA3ETV4 (PEA3/E1AF), ETV5 (ERM), ETV1 (ER81)
ER71ETV2 (ER71)
SPISPI1 (PU.1), SPIB, SPIC
TCFELK1, ELK4 (SAP1), ELK3 (NET/SAP2) LIN
TELETV6 (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]

Further reading

Notes and References

  1. 10.1038/306391a0 . Nunn . M. F. . Seeburg . P. H. . Moscovici . C. . Duesberg . P. H. . Tripartite structure of the avian erythroblastosis virus E26 transforming gene . Nature . 306 . 5941 . 391–395 . 1983 . 6316155. 1983Natur.306..391N . 4302399 .
  2. 10.1038/306395a0 . Leprince . D. . Gegonne . A. . Coll . J. . De Taisne . C. . Schneeberger . A. . Lagrou . C. . Stehelin . D. . A putative second cell-derived oncogene of the avian leukaemia retrovirus E26 . Nature . 306 . 5941 . 395–397 . 1983 . 6316156. 1983Natur.306..395L . 4318034 .
  3. 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 . en . 17 . 6 . 337–351 . 10.1038/nrc.2017.20 . 28450705 . 1474-1768.
  4. Gutierrez-Hartman A, Duval DL, Bradford AP . ETS transcription factors in endocrine systems . Trends Endocrinol Metab . 18 . 4 . 150–8 . 2007 . 17387021 . 10.1016/j.tem.2007.03.002 . 24617218 .
  5. Ida K, Kobayashi S, Taki T, Hanada R, Bessho F, Yamamori S, Sugimoto T, Ohki M, Hayashi Y . EWS-FLI-1 and EWS-ERG chimeric mRNAs in Ewing's sarcoma and primitive neuroectodermal tumor . Int J Cancer . 63 . 4 . 500–4 . 1995 . 7591257 . 10.1002/ijc.2910630407. 24841690 .
  6. 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 . 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 . 1997 . 10.1182/blood.V90.7.2535 . 9326218 . free .
  7. 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 . Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer . . 310 . 5748 . 644–8 . October 2005 . 16254181 . 10.1126/science.1117679 . 2005Sci...310..644T . 85788789 .
  8. Flames N, Hobert O . Gene regulatory logic of dopaminergic neuron differentiation . Nature . 458 . 885–890 . 2009 . 10.1038/nature07929 . 19287374 . 7240 . 2671564.
  9. Verger A, Duterque-Coquillaud M . When Ets transcription factors meet their partners . BioEssays . 24 . 4 . 362–70 . 2002 . 11948622 . 10.1002/bies.10068 .
  10. Sharrocks AD . The ETS-domain transcription factor family . Nat Rev Mol Cell Biol . 2 . 11 . 827–37 . 2001 . 11715049 . 10.1038/35099076 . 5407789 .

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