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CRE-decoy oligonucleotide-inhibition of gene expression and tumor growth

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Abstract

Nucleic acid molecules with high affinities for a target transcription factor can be introduced into cells as decoy cis-elements to bind these factors and alter gene expression. This review discusses a synthetic single-stranded palindromic oligonucleotide, which self-hybridizes to form a duplex/hairpin and competes with cAMP response element (CRE) enhancers for binding transcription factors. This oligonucleotide inhibits CRE- and Ap-1-directed gene transcription and promotes growth inhibition in vitro and in vivo in a broad spectrum of cancer cells, without adversely affecting normal cell growth. Evidence presented here suggests that the CRE-decoy oligonucleotide can provide a powerful new means of combating cancers, viral diseases, and other pathological conditions by regulating the expression of cAMP-responsive genes.

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References

  1. Hu MC-T, Davidson N: The inducible lac operator-repressor system is functional in mammalian cells. Cell 48: 555–566, 1987

    Google Scholar 

  2. Brown M, Figge J, Hansen U, Wright C, Jeang K-T, Khoury G, Livingston DM, Roberts TM: Lac repressor can regulate expression from a hybrid SV40 early promoter containing a lac operator in animal cells. Cell 49: 603–612, 1987

    Google Scholar 

  3. Friedman AD, Triezenberg SJ, McKnight SL: Expression of a truncated viral trans-activator selectively impedes lytic infection by its cognate virus. Nature 335: 452–454, 1988

    Google Scholar 

  4. Wang XF, Calame K: SV40 enhancer-binding factors are required at the establishment but not the maintenance step of enhancer-dependent transcriptional activation. Cell 47: 241–247, 1986

    Google Scholar 

  5. Maher LJ, Wold B, Dervan PB: Inhibition of DNA binding proteins by oligonucleotide-directed triple helix formation. Science 245: 725–730, 1989

    Google Scholar 

  6. Zon G: Oligonucleotide analogues as potential chemotherapeutic agents. Pharm Res 5: 539–549, 1988

    Google Scholar 

  7. Agrawal S, Jiang Z, Zhao Q, Shaw D, Cai Q, Roskey A, Channavajjala L, Saxinger C, Zhang R: Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: In vitro and in vivo studies. Proc Natl Acad Sci USA 94: 2620–2625, 1997

    Google Scholar 

  8. Crooke ST: Therapeutic applications of oligonucleotides. Annu Rev Pharmacol Toxicol 32: 329–376, 1992

    Google Scholar 

  9. Agrawal S, Zhao Q: Antisense therapeutics. Curr Opin Chem Biol 2: 519–528, 1998

    Google Scholar 

  10. Bielinska A, Shivdasani RA, Zhang L, Nabel GJ: Regulation of gene expression with double-stranded phosphorothioate oligonucleotides. Science 250: 997–1000, 1990

    Google Scholar 

  11. Morishita R, Gibbons GH, Horiuchi M, Ellison KE, Nakajima M, Zhang L, Kaneda Y, Ogihara T, Dzau VJ: A novel molecular strategy using cis element ‘decoy’ of E2F binding site inhibits smooth muscle proliferation in vivo. Proc Natl Acad Sci USA 92: 5855–5859, 1995

    Google Scholar 

  12. Roesler WJ, Vandenbark GR, Hanson RW: Cyclic AMP and the induction of eukaryotic gene transcription. J Biol Chem 263: 9063–9066, 1988

    Google Scholar 

  13. Park YG, Nesterova M, Agrawal S, Cho-Chung YS: Dual blockade of cyclic AMP responsive element-(CRE) and AP-1-directed transcription by CRE-transcription factor decoy oligonucleotide. J Biol Chem 274: 1573–1580, 1999

    Google Scholar 

  14. Montminy MR, Bilezikjian LM: Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature 328: 175–178, 1987

    Google Scholar 

  15. Montminy MR, Sevarino KA, Wagner JA, Mandel G, Goodman RH: Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc Natl Acad Sci USA 83: 6682–6686, 1986

    Google Scholar 

  16. Maniatis T, Goodbourn S, Fischer JA: Regulation of inducible and tissue-specific gene expression. Science 236: 1237–1245, 1987

    Google Scholar 

  17. Short JM, Wynshaw-Boris A, Short HP, Hanson RW: Characterization of the phosphoenolpyruvate carboxykinase (GTP) promoter-regulatory region. II. Identification of cAMP and glucocortcoid regulatory domains. J Biol Chem 261: 9721–9726, 1986

    Google Scholar 

  18. Habener JF: Cyclic AMP response element binding proteins: A cornucopia of transcription factors. Mol Endocrinol 4: 1087–1094, 1990

    Google Scholar 

  19. Rauscher FJ, Sambucetti LC, Curran T, Distel RJ, Spieglman BM: Common DNA binding site for Fos protein complexes and transcription factor AP-1. Cell 52: 471–480, 1988

    Google Scholar 

  20. Ellis MJC, Hurst HC, Goodbourn SA: A novel cyclic AMP response element-binding protein-1 (CREB-1) splice product may down-regulate CREB-1 activity. J Mol Endocrinol 14: 191–198, 1995

    Google Scholar 

  21. Stein CA: Does antisense exist? Nature Med 1: 1119–1121, 1995

    Google Scholar 

  22. Gonzalez GA, Montminy MR: Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59: 675–680, 1989

    Google Scholar 

  23. Walton KM, Rehfuss RP, Chrivia JC, Lochner JE, Goodman RH: A dominant repressor of cyclic adenosine 3′,5′-monophosphate (cAMP)-regulated enhancer-binding protein activity inhibits the cAMP-mediated induction of the somatostatin promoter in vivo. Mol Endocrinol 6: 647–655, 1992

    Google Scholar 

  24. Lee YN, Park YG, Choi YH, Cho YS, Cho-Chung YS: CRE-transcription factor decoy oligonucleotide inhibition of MCF-7 breast cancer cells: Cross talk with p53 signaling pathway. Biochemistry 39: 4863–4868, 2000

    Google Scholar 

  25. Amsterdam A, Keren-Tal I, Aharoni D: Cross-talk between cAMP and p53-generated signals in induction of differentiation and apoptosis in steroidogenic granulosa cells. Steroids 61: 252–256, 1996

    Google Scholar 

  26. Keren-Tal I, Suh B-S, Dantes A, Lindner S, Oren M, Amsterdam A: Involvement of p53 expression in cAMP-mediated apoptosis in immortalized granulosa cells. Exp Cell Res 218: 283–295, 1995

    Google Scholar 

  27. Haldar S, Negrini M, Monne M, Sabbioni S, Croce CM: Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res 54: 2095–2097, 1994

    Google Scholar 

  28. von Knethen A, Lotero A, Brune B: Etoposide and cisplatin induced apoptosis in activated RAW 264.7 macrophages is attenuated by cAMPinduced gene expression. Oncogene 387–394, 1998

  29. Chrivia JC, Kwok RPS, Lamb N, Hagiwara M, Montminy MR, Goodman RH: Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365: 819–823, 1993

    Google Scholar 

  30. Kwok RPS, Lundblad JR, Chrivia JC, Richards JP, Bachinger HP, Brennan RG, Roberts SGE, Green MR, Goodman RH: Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370: 223–226, 1994

    Google Scholar 

  31. Arias J, Alberts AS, Brindle P, Claret FX, Smeal T, Karin M, Feramisco J, Montminy M: Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature 370: 226–229, 1994

    Google Scholar 

  32. Gu W, Shi XL, Roeder RG: Synergistic activation of transcription by CBP and p53. Nature 387: 819–523, 1997

    Google Scholar 

  33. Agadir A, Shealy YF, Hill DL, Zhang X: Retinyl methyl ether downregulates activator protein 1 transcriptional activation in breast cancer cells. Cancer Res 57: 3444–3450, 1997

    Google Scholar 

  34. McMurray CT, Wilson WD, Douglass JO: Hairpin formation within the enhancer region of the human enkephalin gene. Proc Natl Acad Sci USA 88: 666–670, 1991

    Google Scholar 

  35. Gacy AM, McMurray CT: Hairpin formation within the human enkephalin enhancer region. Kinetic Anal Biochem 33: 11951–11959, 1994

    Google Scholar 

  36. Comb M, Mermod N, Hyman SE, Pearlberg J, Ross ME, Goodman HM: Proteins bound at adjacent DNA elements act synergistically to regulate human proenkephalin cAMP inducible transcription. EMBO J 7: 3793–3805, 1988

    Google Scholar 

  37. Bazett-Jones DP, Brown ML: Electron microscopy reveals that transcription factor TFIIIA bends 5S DNA. Mol Cell Biol 9: 336–341, 1989

    Google Scholar 

  38. Kerppola TK, Curran T: DNA bending by Fos and Jun: The flexible hinge model. Science 354: 1210–1214, 1991

    Google Scholar 

  39. Perez-Martin J, Espinoza M: Protein-induced bending as a transcriptional switch. Science 260: 805–807, 1993

    Google Scholar 

  40. Horwitz MSZ, Loeb LA: An E. coli promoter that regulates transcription by DNA superhelix-induced cruciform extrusion. Science 241: 703–705, 1988

    Google Scholar 

  41. Bianchi ME, Beltrame M, Paonessa G: Specific recognition of cruciform DNA by nuclear protein HMG1. Science 243: 1056–1059, 1989

    Google Scholar 

  42. Glucksmann MA, Markiewicz P, Malone C, Rothman-Denes LB: Specific sequences and a hairpin structure in the template strand are required for N4 viron RNA polymerase promoter recognition. Cell 70: 491–500, 1992

    Google Scholar 

  43. Sun P, Enslen H, Myung PS, Maurer RA: Differential activation of CREB by Ca2+/calmodulin-dependent protein kinases type II and type IV involves phosphorylation of a site that negatively regulates activity. Genes Dev 8: 2527–2539, 1994

    Google Scholar 

  44. Xing J, Ginty DD, Greenberg ME: Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273: 959–963, 1996

    Google Scholar 

  45. Sheng M, Thomson MA, Greenberg ME: CREB: A Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252: 1427–1430, 1991

    Google Scholar 

  46. Ginty DD, Bonni A, Greenberg ME: Nerve growth factor activates a ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell 77: 713–725, 1994

    Google Scholar 

  47. Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ: FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 15: 4629–4642, 1996

    Google Scholar 

  48. Nilsson M, Ford J, Bohm S, Toftgard R: Characterization of a nuclear factor that binds juxtaposed with ATF3/Jun on a composite response element specifically mediating induced transcription in response to an epidermal growth factor/Ras/Raf signaling pathway. Cell Growth Diff 8: 913–920, 1997.

    Google Scholar 

  49. Williams JS, Andrisani OM: The hepatitis B virus X protein targets the basic region-leucine zipper domain of CREB. Proc Natl Acad Sci USA 92: 3819–3823, 1995

    Google Scholar 

  50. Jeang K-T, Boros I, Brady J, Radonovich M, Khoury G: Characterization of cellular factors that interact with the human T-cell leukemia virus type I p40-responsive 21-base-pair sequence. J Virol 62: 4499–4509, 1988

    Google Scholar 

  51. Nakamura M, Niki M, Obtani K, Sugamura K: Differential activation of the 21-base-pair enhancer element of human T-cell leukemia virus type I by its own trans-activator and cyclic AMP. Nucleic Acids Res 17: 5207–5221, 1989

    Google Scholar 

  52. Poteat HT, Kadison P, McGuire K, Park L, Park RE, Sodroski JG, Haseltine WA: Response of the human T-cell leukemia virus type 1 long terminal repeat to cyclic AMP. J Virol 64: 1604–1611, 1989

    Google Scholar 

  53. Niki M, Ohtani K, Nakamura M, Sugamura K: Multistep regulation of enhancer activity of the 21-base-pair element of human T-cell leukemia virus type I. J Virol 66: 4348–4357, 1992

    Google Scholar 

  54. Bodor J, Walker W, Flemington E, Spetz A-L, Habener J: Modulation of Tax and PKA-mediated expression of HTLV-I promoter via cAMP response element binding and modulator proteins CREB and CREM, FEBS Lett 377: 413–418, 1995

    Google Scholar 

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Authors and Affiliations

  1. Cellular Biochemistry Section, Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, MD, 20892-1750, USA

    Yoon S. Cho-Chung

  2. Cellular Biochemistry Section, Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, MD, 20892-1750, USA

    Yun Gyu Park, Maria Nesterova, Youl Nam Lee & Yee Sook Cho

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  1. Yoon S. Cho-Chung
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  2. Yun Gyu Park
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  3. Maria Nesterova
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  4. Youl Nam Lee
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  5. Yee Sook Cho
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Cho-Chung, Y.S., Park, Y.G., Nesterova, M. et al. CRE-decoy oligonucleotide-inhibition of gene expression and tumor growth. Mol Cell Biochem 212, 29–34 (2000). https://doi.org/10.1023/A:1007144618589

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