Abstract
Ets proteins have been implicated in the regulation of gene expression during a variety of biological processes, including growth control, differentiation, development and transformation. More than 35 related proteins containing the 'ets domain' have now been found which specifically interact with DNA sequences encompassing the core tetranucleotide GGAA. Although ets responsive genes have been identified in the epidermis, little is known about their distribution and function in this tissue. We have now demonstrated that epidermis and cultured epidermal keratinocytes synthesize numerous ets proteins. The expression of some of these proteins is regulated as a function of differentiation. Among these is a novel ets transcription factor with a dual DNA-binding specificity, which we have called jen. The expression of jen is not only epithelial specific, but it is the only ets protein so far described, and one of the very few transcription factors whose expression is restricted to the most differentiated epidermal layers. We show that two epidermal marker genes whose expression coincides with that of jen are transregulated by this protein in a complex mode which involves interactions with other transcriptional regulators such as Sp1 and AP1.
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- Ashar H. R., Fejzo M. S., Tkachenko A., Zhou X., Fletcher J. A., Weremowicz S., Morton C. C., Chada K. Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell. 1995 Jul 14;82(1):57–65. doi: 10.1016/0092-8674(95)90052-7. [DOI] [PubMed] [Google Scholar]
- Bassuk A. G., Leiden J. M. A direct physical association between ETS and AP-1 transcription factors in normal human T cells. Immunity. 1995 Aug;3(2):223–237. doi: 10.1016/1074-7613(95)90092-6. [DOI] [PubMed] [Google Scholar]
- Boulukos K. E., 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. doi: 10.1128/mcb.9.12.5718. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brownell J. E., Allis C. D. Special HATs for special occasions: linking histone acetylation to chromatin assembly and gene activation. Curr Opin Genet Dev. 1996 Apr;6(2):176–184. doi: 10.1016/s0959-437x(96)80048-7. [DOI] [PubMed] [Google Scholar]
- Coffer P., de Jonge M., Mettouchi A., Binetruy B., Ghysdael J., Kruijer W. junB promoter regulation: Ras mediated transactivation by c-Ets-1 and c-Ets-2. Oncogene. 1994 Mar;9(3):911–921. [PubMed] [Google Scholar]
- Delattre O., Zucman J., Plougastel B., Desmaze C., Melot T., Peter M., Kovar H., Joubert I., de Jong P., Rouleau G. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992 Sep 10;359(6391):162–165. doi: 10.1038/359162a0. [DOI] [PubMed] [Google Scholar]
- Ernst P., Hahm K., Smale S. T. Both LyF-1 and an Ets protein interact with a critical promoter element in the murine terminal transferase gene. Mol Cell Biol. 1993 May;13(5):2982–2992. doi: 10.1128/mcb.13.5.2982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ferrari S., Harley V. R., Pontiggia A., Goodfellow P. N., Lovell-Badge R., Bianchi M. E. SRY, like HMG1, recognizes sharp angles in DNA. EMBO J. 1992 Dec;11(12):4497–4506. doi: 10.1002/j.1460-2075.1992.tb05551.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fischer D. F., Gibbs S., van De Putte P., Backendorf C. Interdependent transcription control elements regulate the expression of the SPRR2A gene during keratinocyte terminal differentiation. Mol Cell Biol. 1996 Oct;16(10):5365–5374. doi: 10.1128/mcb.16.10.5365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fuchs E., Byrne C. The epidermis: rising to the surface. Curr Opin Genet Dev. 1994 Oct;4(5):725–736. doi: 10.1016/0959-437x(94)90140-x. [DOI] [PubMed] [Google Scholar]
- Fuchs E. Epidermal differentiation: the bare essentials. J Cell Biol. 1990 Dec;111(6 Pt 2):2807–2814. doi: 10.1083/jcb.111.6.2807. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Giese K., Cox J., Grosschedl R. The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell. 1992 Apr 3;69(1):185–195. doi: 10.1016/0092-8674(92)90129-z. [DOI] [PubMed] [Google Scholar]
- Haas S., Steplewski A., Siracusa L. D., Amini S., Khalili K. Identification of a sequence-specific single-stranded DNA binding protein that suppresses transcription of the mouse myelin basic protein gene. J Biol Chem. 1995 May 26;270(21):12503–12510. doi: 10.1074/jbc.270.21.12503. [DOI] [PubMed] [Google Scholar]
- Harrison S. D., Travers A. A. The tramtrack gene encodes a Drosophila finger protein that interacts with the ftz transcriptional regulatory region and shows a novel embryonic expression pattern. EMBO J. 1990 Jan;9(1):207–216. doi: 10.1002/j.1460-2075.1990.tb08097.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jang S. I., Steinert P. M., Markova N. G. Activator protein 1 activity is involved in the regulation of the cell type-specific expression from the proximal promoter of the human profilaggrin gene. J Biol Chem. 1996 Sep 27;271(39):24105–24114. doi: 10.1074/jbc.271.39.24105. [DOI] [PubMed] [Google Scholar]
- Janknecht R., Nordheim A. Elk-1 protein domains required for direct and SRF-assisted DNA-binding. Nucleic Acids Res. 1992 Jul 11;20(13):3317–3324. doi: 10.1093/nar/20.13.3317. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Janknecht R., Nordheim A. Gene regulation by Ets proteins. Biochim Biophys Acta. 1993 Dec 23;1155(3):346–356. doi: 10.1016/0304-419x(93)90014-4. [DOI] [PubMed] [Google Scholar]
- John S., Reeves R. B., Lin J. X., Child R., Leiden J. M., Thompson C. B., Leonard W. J. 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. doi: 10.1128/mcb.15.3.1786. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jousset C., Carron C., Boureux A., Quang C. T., Oury C., Dusanter-Fourt I., Charon M., Levin J., Bernard O., Ghysdael J. 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. EMBO J. 1997 Jan 2;16(1):69–82. doi: 10.1093/emboj/16.1.69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kallunki T., Deng T., Hibi M., Karin M. c-Jun can recruit JNK to phosphorylate dimerization partners via specific docking interactions. Cell. 1996 Nov 29;87(5):929–939. doi: 10.1016/s0092-8674(00)81999-6. [DOI] [PubMed] [Google Scholar]
- Karin M., Hunter T. Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus. Curr Biol. 1995 Jul 1;5(7):747–757. doi: 10.1016/s0960-9822(95)00151-5. [DOI] [PubMed] [Google Scholar]
- Kozak M. The scanning model for translation: an update. J Cell Biol. 1989 Feb;108(2):229–241. doi: 10.1083/jcb.108.2.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee J. H., Jang S. I., Yang J. M., Markova N. G., Steinert P. M. The proximal promoter of the human transglutaminase 3 gene. Stratified squamous epithelial-specific expression in cultured cells is mediated by binding of Sp1 and ets transcription factors to a proximal promoter element. J Biol Chem. 1996 Feb 23;271(8):4561–4568. [PubMed] [Google Scholar]
- Liang H., Mao X., Olejniczak E. T., Nettesheim D. G., Yu L., Meadows R. P., Thompson C. B., Fesik S. W. Solution structure of the ets domain of Fli-1 when bound to DNA. Nat Struct Biol. 1994 Dec;1(12):871–875. doi: 10.1038/nsb1294-871. [DOI] [PubMed] [Google Scholar]
- Lin A., Minden A., Martinetto H., Claret F. X., Lange-Carter C., Mercurio F., Johnson G. L., Karin M. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286–290. doi: 10.1126/science.7716521. [DOI] [PubMed] [Google Scholar]
- Loo S., Rine J. Silencing and heritable domains of gene expression. Annu Rev Cell Dev Biol. 1995;11:519–548. doi: 10.1146/annurev.cb.11.110195.002511. [DOI] [PubMed] [Google Scholar]
- Macleod K., Leprince D., Stehelin D. The ets gene family. Trends Biochem Sci. 1992 Jul;17(7):251–256. doi: 10.1016/0968-0004(92)90404-w. [DOI] [PubMed] [Google Scholar]
- Maher J. F., Nathans D. Multivalent DNA-binding properties of the HMG-1 proteins. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6716–6720. doi: 10.1073/pnas.93.13.6716. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Micklem G., Rowley A., Harwood J., Nasmyth K., Diffley J. F. Yeast origin recognition complex is involved in DNA replication and transcriptional silencing. Nature. 1993 Nov 4;366(6450):87–89. doi: 10.1038/366087a0. [DOI] [PubMed] [Google Scholar]
- Morasso M. I., Jamrich M., Sargent T. D. The homeodomain gene Xenopus Distal-less-like-2 (Xdll-2) is regulated by a conserved mechanism in amphibian and mammalian epidermis. Dev Biol. 1994 Mar;162(1):267–276. doi: 10.1006/dbio.1994.1084. [DOI] [PubMed] [Google Scholar]
- Morasso M. I., Markova N. G., Sargent T. D. Regulation of epidermal differentiation by a Distal-less homeodomain gene. J Cell Biol. 1996 Dec;135(6 Pt 2):1879–1887. doi: 10.1083/jcb.135.6.1879. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakajima K., Kusafuka T., Takeda T., Fujitani Y., Nakae K., Hirano T. Identification of a novel interleukin-6 response element containing an Ets-binding site and a CRE-like site in the junB promoter. Mol Cell Biol. 1993 May;13(5):3027–3041. doi: 10.1128/mcb.13.5.3027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nye J. A., Petersen J. M., Gunther C. V., Jonsen M. D., Graves B. J. 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. doi: 10.1101/gad.6.6.975. [DOI] [PubMed] [Google Scholar]
- Oettgen P., Alani R. M., Barcinski M. A., Brown L., Akbarali Y., Boltax J., Kunsch C., Munger K., Libermann T. A. Isolation and characterization of a novel epithelium-specific transcription factor, ESE-1, a member of the ets family. Mol Cell Biol. 1997 Aug;17(8):4419–4433. doi: 10.1128/mcb.17.8.4419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pearce J. J., Singh P. B., Gaunt S. J. The mouse has a Polycomb-like chromobox gene. Development. 1992 Apr;114(4):921–929. doi: 10.1242/dev.114.4.921. [DOI] [PubMed] [Google Scholar]
- Peixoto A. A., Campesan S., Costa R., Kyriacou C. P. Molecular evolution of a repetitive region within the per gene of Drosophila. Mol Biol Evol. 1993 Jan;10(1):127–139. doi: 10.1093/oxfordjournals.molbev.a039993. [DOI] [PubMed] [Google Scholar]
- Reeves R., Nissen M. S. The A.T-DNA-binding domain of mammalian high mobility group I chromosomal proteins. A novel peptide motif for recognizing DNA structure. J Biol Chem. 1990 May 25;265(15):8573–8582. [PubMed] [Google Scholar]
- Seth A., Papas T. S. The c-ets-1 proto-oncogene has oncogenic activity and is positively autoregulated. Oncogene. 1990 Dec;5(12):1761–1767. [PubMed] [Google Scholar]
- Shore P., Whitmarsh A. J., Bhaskaran R., Davis R. J., Waltho J. P., Sharrocks A. D. Determinants of DNA-binding specificity of ETS-domain transcription factors. Mol Cell Biol. 1996 Jul;16(7):3338–3349. doi: 10.1128/mcb.16.7.3338. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sieweke M. H., 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. doi: 10.1016/s0092-8674(00)81081-8. [DOI] [PubMed] [Google Scholar]
- Sussman D. J., Klingensmith J., Salinas P., Adams P. S., Nusse R., Perrimon N. Isolation and characterization of a mouse homolog of the Drosophila segment polarity gene dishevelled. Dev Biol. 1994 Nov;166(1):73–86. doi: 10.1006/dbio.1994.1297. [DOI] [PubMed] [Google Scholar]
- Uchiumi F., Semba K., Yamanashi Y., Fujisawa J., Yoshida M., Inoue K., Toyoshima K., Yamamoto T. Characterization of the promoter region of the src family gene lyn and its trans activation by human T-cell leukemia virus type I-encoded p40tax. Mol Cell Biol. 1992 Sep;12(9):3784–3795. doi: 10.1128/mcb.12.9.3784. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wasylyk B., Hahn S. L., Giovane A. The Ets family of transcription factors. Eur J Biochem. 1993 Jan 15;211(1-2):7–18. doi: 10.1007/978-3-642-78757-7_2. [DOI] [PubMed] [Google Scholar]
- Whiteside S. T., Goodbourn S. Signal transduction and nuclear targeting: regulation of transcription factor activity by subcellular localisation. J Cell Sci. 1993 Apr;104(Pt 4):949–955. doi: 10.1242/jcs.104.4.949. [DOI] [PubMed] [Google Scholar]
- Zeleznik-Le N. J., Harden A. M., Rowley J. D. 11q23 translocations split the "AT-hook" cruciform DNA-binding region and the transcriptional repression domain from the activation domain of the mixed-lineage leukemia (MLL) gene. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10610–10614. doi: 10.1073/pnas.91.22.10610. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhou P., Byrne C., Jacobs J., Fuchs E. Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate. Genes Dev. 1995 Mar 15;9(6):700–713. doi: 10.1101/gad.9.6.700. [DOI] [PubMed] [Google Scholar]
- van de Wetering M., Oosterwegel M., Dooijes D., Clevers H. Identification and cloning of TCF-1, a T lymphocyte-specific transcription factor containing a sequence-specific HMG box. EMBO J. 1991 Jan;10(1):123–132. doi: 10.1002/j.1460-2075.1991.tb07928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
