Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFR beta oncoprotein.

Author information

Affiliations

  • 1. CNRS UMR 146, Institut Curie-Section de Recherche, Centre Universitaire, Orsay, France.
      Authors
    • Jousset C 1
    (1 author)

ORCIDs linked to this article

The EMBO Journal, 01 Jan 1997, 16(1):69-82
https://doi.org/10.1093/emboj/16.1.69 PMID: 9009269 PMCID: PMC1169615

Free full text in Europe PMC

Abstract 

TEL is a novel member of the ETS family of transcriptional regulators which is frequently involved in human leukemias as the result of specific chromosomal translocations. We show here by co-immunoprecipitation and GST chromatography analyses that TEL and TEL-derived fusion proteins form homotypic oligomers in vitro and in vivo. Deletion mutagenesis identifies the TEL oligomerization domain as a 65 amino acid region which is conserved in a subset of the ETS proteins including ETS-1, ETS-2, FLI-1, ERG-2 and GABP alpha in vertebrates and PNTP2, YAN and ELG in Drosophila. TEL-induced oligomerization is shown to be essential for the constitutive activation of the protein kinase activity and mitogenic properties of TEL-platelet derived growth factor receptor beta (PDGFR beta), a fusion oncoprotein characteristic of the leukemic cells of chronic myelomonocytic leukemia harboring a t(5;12) chromosomal translocation. Swapping experiments in which the TEL oligomerization domain was exchanged by the homologous domains of representative vertebrate ETS proteins including ETS-1, ERG-2 and GABP alpha show that oligomerization is a specific property of the TEL amino-terminal conserved domain. These results indicate that the amino-terminal domain conserved in a subset of the ETS proteins has evolved to generate a specialized protein-protein interaction interface which is likely to be an important determinant of their specificity as transcriptional regulators.

Free full text 

Logo of embojLink to Publisher's site
EMBO J. 1997 Jan 2; 16(1): 69–82.
PMCID: PMC1169615
PMID: 9009269

A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFR beta oncoprotein.

C Jousset, C Carron, A Boureux, C T Quang, C Oury, I Dusanter-Fourt, M Charon, J Levin, O Bernard, and J Ghysdael
Author information Copyright and License information Disclaimer

Abstract

TEL is a novel member of the ETS family of transcriptional regulators which is frequently involved in human leukemias as the result of specific chromosomal translocations. We show here by co-immunoprecipitation and GST chromatography analyses that TEL and TEL-derived fusion proteins form homotypic oligomers in vitro and in vivo. Deletion mutagenesis identifies the TEL oligomerization domain as a 65 amino acid region which is conserved in a subset of the ETS proteins including ETS-1, ETS-2, FLI-1, ERG-2 and GABP alpha in vertebrates and PNTP2, YAN and ELG in Drosophila. TEL-induced oligomerization is shown to be essential for the constitutive activation of the protein kinase activity and mitogenic properties of TEL-platelet derived growth factor receptor beta (PDGFR beta), a fusion oncoprotein characteristic of the leukemic cells of chronic myelomonocytic leukemia harboring a t(5;12) chromosomal translocation. Swapping experiments in which the TEL oligomerization domain was exchanged by the homologous domains of representative vertebrate ETS proteins including ETS-1, ERG-2 and GABP alpha show that oligomerization is a specific property of the TEL amino-terminal conserved domain. These results indicate that the amino-terminal domain conserved in a subset of the ETS proteins has evolved to generate a specialized protein-protein interaction interface which is likely to be an important determinant of their specificity as transcriptional regulators.

Full Text

The Full Text of this article is available as a PDF (590K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Daley GQ, Baltimore D. Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9312–9316. [Europe PMC free article] [Abstract] [Google Scholar]
  • Daley GQ, Van Etten RA, Jackson PK, Bernards A, Baltimore D. Nonmyristoylated Abl proteins transform a factor-dependent hematopoietic cell line. Mol Cell Biol. 1992 Apr;12(4):1864–1871. [Europe PMC free article] [Abstract] [Google Scholar]
  • Dalton S, Treisman R. Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element. Cell. 1992 Feb 7;68(3):597–612. [Abstract] [Google Scholar]
  • Damen JE, Wakao H, Miyajima A, Krosl J, Humphries RK, Cutler RL, Krystal G. Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin-induced cell proliferation and Stat5 activation. EMBO J. 1995 Nov 15;14(22):5557–5568. [Europe PMC free article] [Abstract] [Google Scholar]
  • de Parseval N, Fichelson S, Mayeux P, Gisselbrecht S, Sola B. Expression of functional beta-platelet-derived growth factor receptors on hematopoietic cell lines. Cytokine. 1993 Jan;5(1):8–15. [Abstract] [Google Scholar]
  • Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Kovar H, Joubert I, de Jong P, Rouleau G, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992 Sep 10;359(6391):162–165. [Abstract] [Google Scholar]
  • Delgado MD, Hallier M, Meneceur P, Tavitian A, Moreau-Gachelin F. Inhibition of Friend cells proliferation by spi-1 antisense oligodeoxynucleotides. Oncogene. 1994 Jun;9(6):1723–1727. [Abstract] [Google Scholar]
  • Donaldson LW, Petersen JM, Graves BJ, McIntosh LP. Secondary structure of the ETS domain places murine Ets-1 in the superfamily of winged helix-turn-helix DNA-binding proteins. Biochemistry. 1994 Nov 22;33(46):13509–13516. [Abstract] [Google Scholar]
  • Frangioni JV, Neel BG. Solubilization and purification of enzymatically active glutathione S-transferase (pGEX) fusion proteins. Anal Biochem. 1993 Apr;210(1):179–187. [Abstract] [Google Scholar]
  • Gegonne A, Punyammalee B, Rabault B, Bosselut R, Seneca S, Crabeel M, Ghysdael J. Analysis of the DNA binding and transcriptional activation properties of the Ets1 oncoprotein. New Biol. 1992 May;4(5):512–519. [Abstract] [Google Scholar]
  • Gégonne A, Bosselut R, Bailly RA, Ghysdael J. Synergistic activation of the HTLV1 LTR Ets-responsive region by transcription factors Ets1 and Sp1. EMBO J. 1993 Mar;12(3):1169–1178. [Europe PMC free article] [Abstract] [Google Scholar]
  • Bongarzone I, Monzini N, Borrello MG, Carcano C, Ferraresi G, Arighi E, Mondellini P, Della Porta G, Pierotti MA. Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A. Mol Cell Biol. 1993 Jan;13(1):358–366. [Europe PMC free article] [Abstract] [Google Scholar]
  • Bories JC, Willerford DM, Grévin D, Davidson L, Camus A, Martin P, Stéhelin D, Alt FW. Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene. Nature. 1995 Oct 19;377(6550):635–638. [Abstract] [Google Scholar]
  • Boulukos KE, Pognonec P, Begue A, Galibert F, Gesquière JC, Stéhelin D, Ghysdael J. Identification in chickens of an evolutionarily conserved cellular ets-2 gene (c-ets-2) encoding nuclear proteins related to the products of the c-ets proto-oncogene. EMBO J. 1988 Mar;7(3):697–705. [Europe PMC free article] [Abstract] [Google Scholar]
  • Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. 1994 Apr 22;77(2):307–316. [Abstract] [Google Scholar]
  • Boulukos KE, Pognonec P, Rabault B, Begue A, Ghysdael J. Definition of an Ets1 protein domain required for nuclear localization in cells and DNA-binding activity in vitro. Mol Cell Biol. 1989 Dec;9(12):5718–5721. [Europe PMC free article] [Abstract] [Google Scholar]
  • Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P, Morgan E, Raimondi SC, Rowley JD, Gilliland DG. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4917–4921. [Europe PMC free article] [Abstract] [Google Scholar]
  • Greco A, Pierotti MA, Bongarzone I, Pagliardini S, Lanzi C, Della Porta G. TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas. Oncogene. 1992 Feb;7(2):237–242. [Abstract] [Google Scholar]
  • Brunner D, Dücker K, Oellers N, Hafen E, Scholz H, Klämbt C. The ETS domain protein pointed-P2 is a target of MAP kinase in the sevenless signal transduction pathway. Nature. 1994 Aug 4;370(6488):386–389. [Abstract] [Google Scholar]
  • Gugneja S, Virbasius JV, Scarpulla RC. Four structurally distinct, non-DNA-binding subunits of human nuclear respiratory factor 2 share a conserved transcriptional activation domain. Mol Cell Biol. 1995 Jan;15(1):102–111. [Europe PMC free article] [Abstract] [Google Scholar]
  • Heldin CH. Dimerization of cell surface receptors in signal transduction. Cell. 1995 Jan 27;80(2):213–223. [Abstract] [Google Scholar]
  • McWhirter JR, Galasso DL, Wang JY. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol. 1993 Dec;13(12):7587–7595. [Europe PMC free article] [Abstract] [Google Scholar]
  • Metz T, Graf T. Fusion of the nuclear oncoproteins v-Myb and v-Ets is required for the leukemogenicity of E26 virus. Cell. 1991 Jul 12;66(1):95–105. [Abstract] [Google Scholar]
  • Metz T, Graf T. v-myb and v-ets transform chicken erythroid cells and cooperate both in trans and in cis to induce distinct differentiation phenotypes. Genes Dev. 1991 Mar;5(3):369–380. [Abstract] [Google Scholar]
  • Miyazaki T, Liu ZJ, Kawahara A, Minami Y, Yamada K, Tsujimoto Y, Barsoumian EL, Permutter RM, Taniguchi T. Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. Cell. 1995 Apr 21;81(2):223–231. [Abstract] [Google Scholar]
  • Ichikawa H, Shimizu K, Hayashi Y, Ohki M. An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation. Cancer Res. 1994 Jun 1;54(11):2865–2868. [Abstract] [Google Scholar]
  • Moreau-Gachelin F, Tavitian A, Tambourin P. Spi-1 is a putative oncogene in virally induced murine erythroleukaemias. Nature. 1988 Jan 21;331(6153):277–280. [Abstract] [Google Scholar]
  • Morgenstern JP, Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 1990 Jun 25;18(12):3587–3596. [Europe PMC free article] [Abstract] [Google Scholar]
  • Muthusamy N, Barton K, Leiden JM. Defective activation and survival of T cells lacking the Ets-1 transcription factor. Nature. 1995 Oct 19;377(6550):639–642. [Abstract] [Google Scholar]
  • Jeon IS, Davis JN, Braun BS, Sublett JE, Roussel MF, Denny CT, Shapiro DN. A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene. 1995 Mar 16;10(6):1229–1234. [Abstract] [Google Scholar]
  • Nunn MF, Seeburg PH, Moscovici C, Duesberg PH. Tripartite structure of the avian erythroblastosis virus E26 transforming gene. Nature. 1983 Nov 24;306(5941):391–395. [Abstract] [Google Scholar]
  • Nye JA, Petersen JM, Gunther CV, Jonsen MD, Graves BJ. Interaction of murine ets-1 with GGA-binding sites establishes the ETS domain as a new DNA-binding motif. Genes Dev. 1992 Jun;6(6):975–990. [Abstract] [Google Scholar]
  • John S, Reeves RB, Lin JX, Child R, Leiden JM, Thompson CB, Leonard WJ. Regulation of cell-type-specific interleukin-2 receptor alpha-chain gene expression: potential role of physical interactions between Elf-1, HMG-I(Y), and NF-kappa B family proteins. Mol Cell Biol. 1995 Mar;15(3):1786–1796. [Europe PMC free article] [Abstract] [Google Scholar]
  • O'Neill EM, Rebay I, Tjian R, Rubin GM. The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway. Cell. 1994 Jul 15;78(1):137–147. [Abstract] [Google Scholar]
  • Klämbt C. The Drosophila gene pointed encodes two ETS-like proteins which are involved in the development of the midline glial cells. Development. 1993 Jan;117(1):163–176. [Abstract] [Google Scholar]
  • Pantazis P, Kharbanda S, Goustin AS, Galanopoulos T, Kufe D. Coexpression of the genes for platelet-derived growth factor B-chain receptor and macrophage colony-stimulating factor 1 receptor during monocytic differentiation. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2481–2485. [Europe PMC free article] [Abstract] [Google Scholar]
  • LaMarco K, Thompson CC, Byers BP, Walton EM, McKnight SL. Identification of Ets- and notch-related subunits in GA binding protein. Science. 1991 Aug 16;253(5021):789–792. [Abstract] [Google Scholar]
  • Levin JM, Garnier J. Improvements in a secondary structure prediction method based on a search for local sequence homologies and its use as a model building tool. Biochim Biophys Acta. 1988 Aug 10;955(3):283–295. [Abstract] [Google Scholar]
  • Levin JM, Pascarella S, Argos P, Garnier J. Quantification of secondary structure prediction improvement using multiple alignments. Protein Eng. 1993 Nov;6(8):849–854. [Abstract] [Google Scholar]
  • Prasad DD, Ouchida M, Lee L, Rao VN, Reddy ES. TLS/FUS fusion domain of TLS/FUS-erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain. Oncogene. 1994 Dec;9(12):3717–3729. [Abstract] [Google Scholar]
  • Liang H, Mao X, Olejniczak ET, Nettesheim DG, Yu L, Meadows RP, Thompson CB, Fesik SW. Solution structure of the ets domain of Fli-1 when bound to DNA. Nat Struct Biol. 1994 Dec;1(12):871–875. [Abstract] [Google Scholar]
  • Ma PC, Rould MA, Weintraub H, Pabo CO. Crystal structure of MyoD bHLH domain-DNA complex: perspectives on DNA recognition and implications for transcriptional activation. Cell. 1994 May 6;77(3):451–459. [Abstract] [Google Scholar]
  • Rabault B, Ghysdael J. Calcium-induced phosphorylation of ETS1 inhibits its specific DNA binding activity. J Biol Chem. 1994 Nov 11;269(45):28143–28151. [Abstract] [Google Scholar]
  • Rabault B, Roussel MF, Quang CT, Ghysdael J. Phosphorylation of Ets1 regulates the complementation of a CSF-1 receptor impaired in mitogenesis. Oncogene. 1996 Aug 15;13(4):877–881. [Abstract] [Google Scholar]
  • Rao VN, Ohno T, Prasad DD, Bhattacharya G, Reddy ES. Analysis of the DNA-binding and transcriptional activation functions of human Fli-1 protein. Oncogene. 1993 Aug;8(8):2167–2173. [Abstract] [Google Scholar]
  • May WA, Lessnick SL, Braun BS, Klemsz M, Lewis BC, Lunsford LB, Hromas R, Denny CT. The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1. Mol Cell Biol. 1993 Dec;13(12):7393–7398. [Europe PMC free article] [Abstract] [Google Scholar]
  • Rodrigues GA, Park M. Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase. Mol Cell Biol. 1993 Nov;13(11):6711–6722. [Europe PMC free article] [Abstract] [Google Scholar]
  • Schneikert J, Lutz Y, Wasylyk B. Two independent activation domains in c-Ets-1 and c-Ets-2 located in non-conserved sequences of the ets gene family. Oncogene. 1992 Feb;7(2):249–256. [Abstract] [Google Scholar]
  • Schuetze S, Stenberg PE, Kabat D. The Ets-related transcription factor PU.1 immortalizes erythroblasts. Mol Cell Biol. 1993 Sep;13(9):5670–5678. [Europe PMC free article] [Abstract] [Google Scholar]
  • Scott EW, Simon MC, Anastasi J, Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science. 1994 Sep 9;265(5178):1573–1577. [Abstract] [Google Scholar]
  • Seth A, Papas TS. The c-ets-1 proto-oncogene has oncogenic activity and is positively autoregulated. Oncogene. 1990 Dec;5(12):1761–1767. [Abstract] [Google Scholar]
  • Shimizu K, Ichikawa H, Tojo A, Kaneko Y, Maseki N, Hayashi Y, Ohira M, Asano S, Ohki M. An ets-related gene, ERG, is rearranged in human myeloid leukemia with t(16;21) chromosomal translocation. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10280–10284. [Europe PMC free article] [Abstract] [Google Scholar]
  • Sieweke MH, Tekotte H, Frampton J, Graf T. MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation. Cell. 1996 Apr 5;85(1):49–60. [Abstract] [Google Scholar]
  • Thompson CC, Brown TA, McKnight SL. Convergence of Ets- and notch-related structural motifs in a heteromeric DNA binding complex. Science. 1991 Aug 16;253(5021):762–768. [Abstract] [Google Scholar]
  • Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994 Nov 11;22(22):4673–4680. [Europe PMC free article] [Abstract] [Google Scholar]
  • Quang CT, Pironin M, von Lindern M, Beug H, Ghysdael J. Spi-1 and mutant p53 regulate different aspects of the proliferation and differentiation control of primary erythroid progenitors. Oncogene. 1995 Oct 5;11(7):1229–1239. [Abstract] [Google Scholar]
  • Virbasius JV, Virbasius CA, Scarpulla RC. Identity of GABP with NRF-2, a multisubunit activator of cytochrome oxidase expression, reveals a cellular role for an ETS domain activator of viral promoters. Genes Dev. 1993 Mar;7(3):380–392. [Abstract] [Google Scholar]
  • Wassarman DA, Therrien M, Rubin GM. The Ras signaling pathway in Drosophila. Curr Opin Genet Dev. 1995 Feb;5(1):44–50. [Abstract] [Google Scholar]
  • Wasylyk B, Wasylyk C, Flores P, Begue A, Leprince D, Stehelin D. The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation. Nature. 1990 Jul 12;346(6280):191–193. [Abstract] [Google Scholar]
  • Wasylyk B, Hahn SL, Giovane A. The Ets family of transcription factors. Eur J Biochem. 1993 Jan 15;211(1-2):7–18. [Abstract] [Google Scholar]
  • Watanabe H, Sawada J, Yano K, Yamaguchi K, Goto M, Handa H. cDNA cloning of transcription factor E4TF1 subunits with Ets and notch motifs. Mol Cell Biol. 1993 Mar;13(3):1385–1391. [Europe PMC free article] [Abstract] [Google Scholar]
  • Weiner DB, Liu J, Cohen JA, Williams WV, Greene MI. A point mutation in the neu oncogene mimics ligand induction of receptor aggregation. Nature. 1989 May 18;339(6221):230–231. [Abstract] [Google Scholar]
  • Williams LT. Signal transduction by the platelet-derived growth factor receptor. Science. 1989 Mar 24;243(4898):1564–1570. [Abstract] [Google Scholar]
  • Woods DB, Ghysdael J, Owen MJ. Identification of nucleotide preferences in DNA sequences recognised specifically by c-Ets-1 protein. Nucleic Acids Res. 1992 Feb 25;20(4):699–704. [Europe PMC free article] [Abstract] [Google Scholar]
  • Wotton D, Prosser HM, Owen MJ. Regulation of human T cell receptor beta gene expression by Ets-1. Leukemia. 1993 Aug;7 (Suppl 2):S55–S60. [Abstract] [Google Scholar]
  • Yang BS, Hauser CA, Henkel G, Colman MS, Van Beveren C, Stacey KJ, Hume DA, Maki RA, Ostrowski MC. Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2. Mol Cell Biol. 1996 Feb;16(2):538–547. [Europe PMC free article] [Abstract] [Google Scholar]
  • Zucman J, Melot T, Desmaze C, Ghysdael J, Plougastel B, Peter M, Zucker JM, Triche TJ, Sheer D, Turc-Carel C, et al. Combinatorial generation of variable fusion proteins in the Ewing family of tumours. EMBO J. 1993 Dec;12(12):4481–4487. [Europe PMC free article] [Abstract] [Google Scholar]
Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

Full text links 

Read article at publisher's site: https://doi.org/10.1093/emboj/16.1.69

Read article for free, from open access legal sources, via Unpaywall: https://europepmc.org/articles/pmc1169615?pdf=renderUnpaywall

Citations & impact 

Impact metrics

125
Citations
Jump to Citations

Citations of article over time

Article citations

Go to all (125) article citations

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.