Logo of jvirolPermissionsJournals.ASM.orgJournalJV ArticleJournal InfoAuthorsReviewers
J Virol. 1996 Jan; 70(1): 188–198.
PMCID: PMC189804

The promoter activity of long terminal repeats of the HERV-H family of human retrovirus-like elements is critically dependent on Sp1 family proteins interacting with a GC/GT box located immediately 3' to the TATA box.


The HERV-H family of endogenous retrovirus-like elements is widely distributed in the human genome, with about 1,000 full-length elements and a similar number of solitary long terminal repeats (LTRs). HERV-H LTRs have been shown to direct the transcription of both HERV-H-encoded and adjacent cellular genes. Transcripts of HERV-H elements are especially abundant in placenta, teratocarcinoma cell lines, and cell lines derived from testicular and lung tumors. Here we report that only a subset of HERV-H LTRs display promoter activity in human cell lines and that these LTRs are characterized by the presence of a GC/GT box immediately downstream of the TATA box. This GC/GT box is required for promoter activity, while, surprisingly, the TATA box is dispensable. The ubiquitously expressed transcription factors Sp1 and Sp3 bound to this GC/GT box and stimulated transcription from the promoter-active LTRs in the teratocarcinoma cell line NTera2-D1. However, in HeLa and Drosophila SL-2 cells, Sp1 acted as a transcriptional activator of the LTRs, while Sp3 acted as a repressor of Sp1-mediated transcriptional activation. Cotransfection studies also revealed that the tissue-specific Sp1-related protein BTEB bound to this GC/GT box and stimulated transcription from the LTR promoters in NTera2-D1 cells. These results show that members of the Sp1 protein family are crucial determinants for transcriptional activation of HERV-H LTR promoters and suggest that these proteins may also be involved in determining the tissue-specific expression pattern of HERV-H elements.

Full Text

The Full Text of this article is available as a PDF (643K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Andrews PW. Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro. Dev Biol. 1984 Jun;103(2):285–293. [PubMed]
  • Andrews PW, Damjanov I, Simon D, Banting GS, Carlin C, Dracopoli NC, Føgh J. Pluripotent embryonal carcinoma clones derived from the human teratocarcinoma cell line Tera-2. Differentiation in vivo and in vitro. Lab Invest. 1984 Feb;50(2):147–162. [PubMed]
  • Boller K, König H, Sauter M, Mueller-Lantzsch N, Löwer R, Löwer J, Kurth R. Evidence that HERV-K is the endogenous retrovirus sequence that codes for the human teratocarcinoma-derived retrovirus HTDV. Virology. 1993 Sep;196(1):349–353. [PubMed]
  • Brodsky I, Foley B, Gillespie D. Expression of human endogenous retrovirus (HERV-K) in chronic myeloid leukemia. Leuk Lymphoma. 1993;11 (Suppl 1):119–123. [PubMed]
  • Chiang CM, Roeder RG. Cloning of an intrinsic human TFIID subunit that interacts with multiple transcriptional activators. Science. 1995 Jan 27;267(5197):531–536. [PubMed]
  • Courey AJ, Tjian R. Analysis of Sp1 in vivo reveals multiple transcriptional domains, including a novel glutamine-rich activation motif. Cell. 1988 Dec 2;55(5):887–898. [PubMed]
  • Di Nocera PP, Dawid IB. Transient expression of genes introduced into cultured cells of Drosophila. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7095–7098. [PMC free article] [PubMed]
  • Dynan WS, Tjian R. The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter. Cell. 1983 Nov;35(1):79–87. [PubMed]
  • Emili A, Greenblatt J, Ingles CJ. Species-specific interaction of the glutamine-rich activation domains of Sp1 with the TATA box-binding protein. Mol Cell Biol. 1994 Mar;14(3):1582–1593. [PMC free article] [PubMed]
  • Faisst S, Meyer S. Compilation of vertebrate-encoded transcription factors. Nucleic Acids Res. 1992 Jan 11;20(1):3–26. [PMC free article] [PubMed]
  • Feuchter AE, Freeman JD, Mager DL. Strategy for detecting cellular transcripts promoted by human endogenous long terminal repeats: identification of a novel gene (CDC4L) with homology to yeast CDC4. Genomics. 1992 Aug;13(4):1237–1246. [PubMed]
  • Feuchter A, Mager D. Functional heterogeneity of a large family of human LTR-like promoters and enhancers. Nucleic Acids Res. 1990 Mar 11;18(5):1261–1270. [PMC free article] [PubMed]
  • Feuchter-Murthy AE, Freeman JD, Mager DL. Splicing of a human endogenous retrovirus to a novel phospholipase A2 related gene. Nucleic Acids Res. 1993 Jan 11;21(1):135–143. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Goodchild NL, Freeman JD, Mager DL. Spliced HERV-H endogenous retroviral sequences in human genomic DNA: evidence for amplification via retrotransposition. Virology. 1995 Jan 10;206(1):164–173. [PubMed]
  • Goodchild NL, Wilkinson DA, Mager DL. A human endogenous long terminal repeat provides a polyadenylation signal to a novel, alternatively spliced transcript in normal placenta. Gene. 1992 Nov 16;121(2):287–294. [PubMed]
  • Goodchild NL, Wilkinson DA, Mager DL. Recent evolutionary expansion of a subfamily of RTVL-H human endogenous retrovirus-like elements. Virology. 1993 Oct;196(2):778–788. [PubMed]
  • Gstaiger M, Knoepfel L, Georgiev O, Schaffner W, Hovens CM. A B-cell coactivator of octamer-binding transcription factors. Nature. 1995 Jan 26;373(6512):360–362. [PubMed]
  • Hagen G, Müller S, Beato M, Suske G. Sp1-mediated transcriptional activation is repressed by Sp3. EMBO J. 1994 Aug 15;13(16):3843–3851. [PMC free article] [PubMed]
  • Hagen G, Müller S, Beato M, Suske G. Cloning by recognition site screening of two novel GT box binding proteins: a family of Sp1 related genes. Nucleic Acids Res. 1992 Nov 11;20(21):5519–5525. [PMC free article] [PubMed]
  • Hirose Y, Takamatsu M, Harada F. Presence of env genes in members of the RTVL-H family of human endogenous retrovirus-like elements. Virology. 1993 Jan;192(1):52–61. [PubMed]
  • Ikeda K, Nagano K, Kawakami K. Anomalous interaction of Sp1 and specific binding of an E-box-binding protein with the regulatory elements of the Na,K-ATPase alpha 2 subunit gene promoter. Eur J Biochem. 1993 Nov 15;218(1):195–204. [PubMed]
  • Ikeda K, Nagano K, Kawakami K. Possible implications of Sp1-induced bending of DNA on synergistic activation of transcription. Gene. 1993 Dec 22;136(1-2):341–343. [PubMed]
  • Imataka H, Mizuno A, Fujii-Kuriyama Y, Hayami M. Activation of the human immunodeficiency virus type 1 long terminal repeat by BTEB, a GC box-binding transcription factor. AIDS Res Hum Retroviruses. 1993 Sep;9(9):825–831. [PubMed]
  • Imataka H, Nakayama K, Yasumoto K, Mizuno A, Fujii-Kuriyama Y, Hayami M. Cell-specific translational control of transcription factor BTEB expression. The role of an upstream AUG in the 5'-untranslated region. J Biol Chem. 1994 Aug 12;269(32):20668–20673. [PubMed]
  • Imataka H, Sogawa K, Yasumoto K, Kikuchi Y, Sasano K, Kobayashi A, Hayami M, Fujii-Kuriyama Y. Two regulatory proteins that bind to the basic transcription element (BTE), a GC box sequence in the promoter region of the rat P-4501A1 gene. EMBO J. 1992 Oct;11(10):3663–3671. [PMC free article] [PubMed]
  • Javahery R, Khachi A, Lo K, Zenzie-Gregory B, Smale ST. DNA sequence requirements for transcriptional initiator activity in mammalian cells. Mol Cell Biol. 1994 Jan;14(1):116–127. [PMC free article] [PubMed]
  • Johansen T, Holm T, Bjørklid E. Members of the RTVL-H family of human endogenous retrovirus-like elements are expressed in placenta. Gene. 1989 Jul 15;79(2):259–267. [PubMed]
  • Kageyama R, Pastan I. Molecular cloning and characterization of a human DNA binding factor that represses transcription. Cell. 1989 Dec 1;59(5):815–825. [PubMed]
  • Kim JL, Nikolov DB, Burley SK. Co-crystal structure of TBP recognizing the minor groove of a TATA element. Nature. 1993 Oct 7;365(6446):520–527. [PubMed]
  • Kim Y, Geiger JH, Hahn S, Sigler PB. Crystal structure of a yeast TBP/TATA-box complex. Nature. 1993 Oct 7;365(6446):512–520. [PubMed]
  • Kingsley C, Winoto A. Cloning of GT box-binding proteins: a novel Sp1 multigene family regulating T-cell receptor gene expression. Mol Cell Biol. 1992 Oct;12(10):4251–4261. [PMC free article] [PubMed]
  • Krieg AM, Gourley MF, Perl A. Endogenous retroviruses: potential etiologic agents in autoimmunity. FASEB J. 1992 May;6(8):2537–2544. [PubMed]
  • Lee KA, Bindereif A, Green MR. A small-scale procedure for preparation of nuclear extracts that support efficient transcription and pre-mRNA splicing. Gene Anal Tech. 1988 Mar-Apr;5(2):22–31. [PubMed]
  • Leib-Mösch C, Bachmann M, Brack-Werner R, Werner T, Erfle V, Hehlmann R. Expression and biological significance of human endogenous retroviral sequences. Leukemia. 1992;6 (Suppl 3):72S–75S. [PubMed]
  • Liu AY, Abraham BA. Subtractive cloning of a hybrid human endogenous retrovirus and calbindin gene in the prostate cell line PC3. Cancer Res. 1991 Aug 1;51(15):4107–4110. [PubMed]
  • Löwer R, Boller K, Hasenmaier B, Korbmacher C, Müller-Lantzsch N, Löwer J, Kurth R. Identification of human endogenous retroviruses with complex mRNA expression and particle formation. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4480–4484. [PMC free article] [PubMed]
  • Löwer R, Löwer J, Tondera-Koch C, Kurth R. A general method for the identification of transcribed retrovirus sequences (R-U5 PCR) reveals the expression of the human endogenous retrovirus loci HERV-H and HERV-K in teratocarcinoma cells. Virology. 1993 Feb;192(2):501–511. [PubMed]
  • Löwer R, Tönjes RR, Korbmacher C, Kurth R, Löwer J. Identification of a Rev-related protein by analysis of spliced transcripts of the human endogenous retroviruses HTDV/HERV-K. J Virol. 1995 Jan;69(1):141–149. [PMC free article] [PubMed]
  • Luckow B, Schütz G. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Res. 1987 Jul 10;15(13):5490–5490. [PMC free article] [PubMed]
  • Lundin M, Nehlin JO, Ronne H. Importance of a flanking AT-rich region in target site recognition by the GC box-binding zinc finger protein MIG1. Mol Cell Biol. 1994 Mar;14(3):1979–1985. [PMC free article] [PubMed]
  • Mager DL. Polyadenylation function and sequence variability of the long terminal repeats of the human endogenous retrovirus-like family RTVL-H. Virology. 1989 Dec;173(2):591–599. [PubMed]
  • Mager DL, Goodchild NL. Homologous recombination between the LTRs of a human retrovirus-like element causes a 5-kb deletion in two siblings. Am J Hum Genet. 1989 Dec;45(6):848–854. [PMC free article] [PubMed]
  • Mager DL, Henthorn PS. Identification of a retrovirus-like repetitive element in human DNA. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7510–7514. [PMC free article] [PubMed]
  • Majello B, De Luca P, Hagen G, Suske G, Lania L. Different members of the Sp1 multigene family exert opposite transcriptional regulation of the long terminal repeat of HIV-1. Nucleic Acids Res. 1994 Nov 25;22(23):4914–4921. [PMC free article] [PubMed]
  • Medstrand P, Lindeskog M, Blomberg J. Expression of human endogenous retroviral sequences in peripheral blood mononuclear cells of healthy individuals. J Gen Virol. 1992 Sep;73(Pt 9):2463–2466. [PubMed]
  • Mueller-Lantzsch N, Sauter M, Weiskircher A, Kramer K, Best B, Buck M, Grässer F. Human endogenous retroviral element K10 (HERV-K10) encodes a full-length gag homologous 73-kDa protein and a functional protease. AIDS Res Hum Retroviruses. 1993 Apr;9(4):343–350. [PubMed]
  • Parvin JD, McCormick RJ, Sharp PA, Fisher DE. Pre-bending of a promoter sequence enhances affinity for the TATA-binding factor. Nature. 1995 Feb 23;373(6516):724–727. [PubMed]
  • Ptashne M. How eukaryotic transcriptional activators work. Nature. 1988 Oct 20;335(6192):683–689. [PubMed]
  • Sauter M, Schommer S, Kremmer E, Remberger K, Dölken G, Lemm I, Buck M, Best B, Neumann-Haefelin D, Mueller-Lantzsch N. Human endogenous retrovirus K10: expression of Gag protein and detection of antibodies in patients with seminomas. J Virol. 1995 Jan;69(1):414–421. [PMC free article] [PubMed]
  • Seed B, Sheen JY. A simple phase-extraction assay for chloramphenicol acyltransferase activity. Gene. 1988 Jul 30;67(2):271–277. [PubMed]
  • Smale ST, Schmidt MC, Berk AJ, Baltimore D. Transcriptional activation by Sp1 as directed through TATA or initiator: specific requirement for mammalian transcription factor IID. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4509–4513. [PMC free article] [PubMed]
  • Sogawa K, Imataka H, Yamasaki Y, Kusume H, Abe H, Fujii-Kuriyama Y. cDNA cloning and transcriptional properties of a novel GC box-binding protein, BTEB2. Nucleic Acids Res. 1993 Apr 11;21(7):1527–1532. [PMC free article] [PubMed]
  • St-Arnaud R, Moir JM. Wnt-1-inducing factor-1: a novel G/C box-binding transcription factor regulating the expression of Wnt-1 during neuroectodermal differentiation. Mol Cell Biol. 1993 Mar;13(3):1590–1598. [PMC free article] [PubMed]
  • Sypes MA, Gilmour DS. Protein/DNA crosslinking of a TFIID complex reveals novel interactions downstream of the transcription start. Nucleic Acids Res. 1994 Mar 11;22(5):807–814. [PMC free article] [PubMed]
  • Vogetseder W, Dumfahrt A, Mayersbach P, Schönitzer D, Dierich MP. Antibodies in human sera recognizing a recombinant outer membrane protein encoded by the envelope gene of the human endogenous retrovirus K. AIDS Res Hum Retroviruses. 1993 Jul;9(7):687–694. [PubMed]
  • Wilkinson DA, Freeman JD, Goodchild NL, Kelleher CA, Mager DL. Autonomous expression of RTVL-H endogenous retroviruslike elements in human cells. J Virol. 1990 May;64(5):2157–2167. [PMC free article] [PubMed]
  • Wilkinson DA, Goodchild NL, Saxton TM, Wood S, Mager DL. Evidence for a functional subclass of the RTVL-H family of human endogenous retrovirus-like sequences. J Virol. 1993 Jun;67(6):2981–2989. [PMC free article] [PubMed]
  • Williams T, Tjian R. Analysis of the DNA-binding and activation properties of the human transcription factor AP-2. Genes Dev. 1991 Apr;5(4):670–682. [PubMed]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...