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Complex regulation of acetylcholinesterase gene expression in human brain tumors

Oncogene volume 21, pages 8428–8441 (2002)Cite this article

Abstract

To study the regulation of acetylcholinesterase (AChE) gene expression in human brain tumors, 3′ splice variants of AChE mRNA and potentially relevant transcription factor mRNAs were labeled in primary astrocytomas and melanomas. AChE-S and AChE-R mRNA, as well as Runx1/AML1 mRNA accumulated in astrocytomas in correlation with tumor aggressiveness, but neither HNF3β nor c-fos mRNA was observed in melanoma and astrocytomas. Immunohistochemistry demonstrated nuclear Runx1/AML1 and cellular AChE-S and AChE-R in melanomas, however, only AChE-S, and not the secreted AChE-R variant, was retained in astrocyte tumor cells. Runx1/AML1 revealed weak linkage with ACHE promoter sequences, yet enhanced ACHE gene expression in co-transfected COS1 cells. The p300 co-activator and the ACHE promoter's distal enhancer facilitated this effect, which was independent of much of the Runx1/AML1 trans-activation domain. Surprisingly, GASP, a fusion product of green fluorescence protein (GFP) and ASP67, a peptide composed of the 67 C-terminal amino acid residues of AChE-S, localized to COS1 cell nuclei. However, GARP, the corresponding fusion product of GFP with a peptide having the 51 C-terminal residues of AChE-E or GFP alone, remained cytoplasmic. Runx1/AML1 exhibited improved nuclear retention in GASP-expressing COS1 cells, suggesting modulated nuclear localization processes. Together, these findings reveal brain tumor-specific regulation of both expression and cellular retention of variant ACHE gene products.

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References

  • Acheson AL, Naujoks K, Thoenen H . 1984 J. Neurosci. 4: 1771–1780

  • Barbosa M, Rios O, Velasquez M, Villalobos J, Ehrmanns J . 2001 Surg. Neurol. 55: 106–112

  • Beeri R, Andres C, Lev-Lehman E, Timberg R, Huberman T, Shani M, Soreq H . 1995 Curr. Biol. 5: 1063–1071

  • Ben Aziz Aloya R, Seidman S, Timberg R, Sternfeld M, Zakut H, Soreq H . 1993 Proc. Natl. Acad. Sci. USA 90: 2471–2475

  • Ben Aziz-Aloya RB, Levanon D, Karn H, Kidron D, Goldenberg D, Lotem J, Polak-Chaklon S, Groner Y . 1998 Cell Growth Differ. 5: 765–773

  • Berger R, Bloomfield CD, Sutherland GR . 1985 Cytogenet. Cell Genet. 40: 490–535

  • Bigbee JW, Sharma KV, Gupta JJ, Dupree JL . 1999 Environ. Health Perspect. 107: Suppl 1 81–87

  • Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, LM S, Burmeister LF, Van Lier SF, Dick F . 1990 Cancer Res. 50: 6585–6591

  • Chan RY, Boudreau-Lariviere C, Angus LM, Mankal FA, Jasmin BJ . 1999 Proc. Natl. Acad. Sci. USA 96: 4627–4632

  • Coleman BA, Taylor P . 1996 J. Biol. Chem. 271: 4410–4416

  • Daumas-Duport C, Scheithauer B, O'Fallon J, Kelly P . 1988 Cancer 62: 2152–2165

  • Duffy JB, Kania MA, Gergen JP . 1991 Development 113: 1223–1230

  • Eckner R, Ewen ME, Newsome D, Gerdes M, DeCaprio JA, Lawrence JB, Livingston DM . 1994 Genes Dev. 8: 869–884

  • Ehrlich G, Viegas Piquignot E, Ginzberg D, Sindel L, Soreq H, Zakut H . 1992 Genomics 13: 1192–1197

  • Etoh T, Inoue H, Yoshikawa Y, Barnard GF, Kitano S, Mori M . 2000 Gut 47: 50–56

  • Getman DK, Eubanks JH, Camp S, Evans GA, Taylor P . 1992 Am. J. Hum. Genet. 51: 170–177

  • Getman D, Mutero A, Inoue K, Taylor P . 1995 J. Biol. Chem. 270: 23511–23519

  • Goodman RH, Smolik S . 2000 Genes Dev. 14: 1553–1577

  • Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A . 1998 Blood 92: 2322–2333

  • Grisaru D, Deutch V, Shapira M, Pick M, Sternfeld M, Melamed-Book N, Kaufer D, Galyam N, Gait M, Owen D, Lessing J, Eldor A, Soreq H . 2001 Molecular Medicine 7: 93–105

  • Grisaru D, Lev-Lehman E, Shapira M, Chaikin E, Lessing JB, Eldor A, Eckstein F, Soreq H . 1999a Mol. Cell. Biol. 19: 788–795

  • Grisaru D, Sternfeld M, Eldor A, Glick D, Soreq H . 1999b Eur. J. Biochem. 264: 672–686

  • Haas R, Jackson BC, Reinhold B, Foster JD, Rosenberry TL . 1996 Biochem. J. 314: 817–825

  • Karpel R, Ben Aziz-Aloya R, Sternfeld M, Ehrlich G, Ginzberg D, Tarroni P, Clementi F, Zakut H, Soreq H . 1994 Exp. Cell Res. 210: 268–277

  • Karpel R, Sternfeld M, Ginzberg D, Guhl E, Graessmann A, Soreq H . 1996 J. Neurochem. 66: 114–123

  • Kataoka H, Ochi M, Enomoto K, Yamaguchi A . 2000 Mech. Dev. 98: 139–143

  • Kaufer D, Friedman A, Seidman S, Soreq H . 1998 Nature 393: 373–377

  • Kitabayashi I, Yokoyama A, Shimizu K, Ohki M . 1998 EMBO J. 17: 2994–3004

  • Kitange G, Kishikawa M, Nakayama T, Naito S, Iseki M, Shibata S . 1999 Mod. Pathol. 12: 618–626

  • Koenigsberger C, Chiappa S, Brimijoin S . 1997 J. Neurochem. 69: 1389–1397

  • Lapidot Lifson Y, Prody CA, Ginzberg D, Meytes D, Zakut H, Soreq H . 1989 Proc. Natl. Acad. Sci. USA 86: 4715–4719

  • Le Beau MM, Espinosa IIIR, Davis EM, Eisenbart JD, Larson RA, Green ED . 1996 Blood 88: 1930–1935

  • Li Y, Camp S, Rachinsky TL, Getman D, Taylor P . 1991 J. Biol. Chem. 266: 23083–23090

  • Li Y, Liu L, Kang J, Sheng JG, Barger SW, Mrak RE, Griffin WS . 2000 J. Neurosci. 20: 149–155

  • Look AT . 1997 Science 278: 1059–1064

  • Meshorer E, Erb C, Gazit R, Pavlovsky L, Kaufer D, Friedman A, Glick D, Ben-Arie N, Soreq H . 2002 Science 295: 508–512

  • Meyers S, Lenny N, Hiebert SW . 1995 Mol. Cell. Biol. 15: 1974–1982

  • Namba K, Abe M, Saito S, Satake M, Ohmoto T, Watanabe T, Sato Y . 2000 Oncogene 19: 106–114

  • Neskovic-Konstantinovic Z, Nikolic-Vukosavljevic D, Brankovic-Magic M, Kanjer K, Gavrilovic D, Mitrovic L, Borojevic N, Vukotic D, Spuzic I . 1999 J. Exp. Clin. Cancer Res. 18: 347–355

  • Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR . 1996 Cell 84: 321–330

  • Perry C, Eldor A, Soreq H . 2002 Leuk. Research 26: 221–228

  • Quandt K, Frech K, Karas H, Wingender E, Werner T . 1995 Nucleic Acids Res. 23: 4878–4884

  • Razon N, Soreq H, Roth E, Bartal A, Silman I . 1984 Experimental Neurology 84: 681–695

  • Rolhion C, Penault-Llorca F, Kemeny JL, Lemaire JJ, Jullien C, Labit-Bouvier C, Finat-Duclos F, Verrelle P . 2001 J. Neurosurg. 94: 97–101

  • Saez-Valero J, Poza-Cisneros G, Vidal CJ . 1996 Neurosci. Lett. 206: 173–176

  • Saez-Valero J, Vidal CJ . 1996 Biochim. Biophys. Acta 1317: 210–218

  • Seidman S, Sternfeld M, Ben Aziz-Aloya R, Timberg R, Kaufer-Nachum D, Soreq H . 1995 Mol. Cell. Biol. 15: 2993–3002

  • Shapira M, Tur-Kaspa I, Bosgraaf L, Livni N, Grant AD, Grisaru D, Korner M, Ebstein RP, Soreq H . 2000 Hum. Mol. Genet. 9: 1273–1281

  • Shohami E, Kaufer D, Chen Y, Seidman S, Cohen O, Ginzberg D, Melamed-Book N, Yirmiya R, Soreq H . 2000 J. Mol. Med. 78: 228–236

  • Silverman E, Eimerl S, Orly J . 1999 J. Biol. Chem. 274: 17987–17996

  • Soreq H, Seidman S . 2001 Nat. Rev. Neurosci. 2: 294–302

  • Soreq H, Zevin-Sonkin D, Razon N . 1984 EMBO J. 3: 1371–1375

  • Sternfeld M, Shoham S, Klein O, Flores-Flores C, Evron T, Idelson GH, Kitsberg D, Patrick JW, Soreq H . 2000 Proc. Natl. Acad. Sci. USA 97: 8647–8652

  • Valter MM, Hugel A, Huang HJ, Cavenee WK, Wiestler OD, Pietsch T, Wernert N . 1999 Cancer Res. 59: 5608–5614

  • Velan B, Kronman C, Flashner Y, Shafferman A . 1994 J. Biol. Chem. 269: 22719–22725

  • Welker P, Schadendorf D, Artuc M, Grabbe J, Henz BM . 2000 Br. J. Cancer 82: 1453–1458

  • Westendorf JJ, Hiebert SW . 1999 J. Cell. Biochem. Suppl 32/33: 51–58

  • Westendorf JJ, Yamamoto CM, Lenny N, Downing JR, Selsted ME, Hiebert SW . 1998 Mol. Cell. Biol. 18: 322–333

  • Yamada M, Ikeuchi T, Aimoto S, Hatanaka H . 1996 J. Neurosci. Res. 43: 355–364

  • Zakut H, Even L, Birkenfeld S, Malinger G, Zisling R, Soreq H . 1988 Cancer 61: 727–737

  • Zhang HT, Scott PA, Morbidelli L, Peak S, Moore J, Turley H, Harris AL, Ziche M, Bicknell R . 2000 Br. J. Cancer 83: 63–68

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Acknowledgements

We are grateful to Drs Yoram Groner, Ditsa Levanon and Varda Negreanu (Rehovot) for the Runx1/AML1 vectors and antibodies, assistance with experiments and fruitful discussions; to Dr Richard H Goodman (Portland, OR, USA) for the p300 plasmid, to Dr A Levitzki (Jerusalem) for human glioblastoma cell lines, and to Dr David Glick (Jerusalem) for reviewing this manuscript. The study was supported by the U.S. Army Medical Research and Materiel Command (DAMD 17-99-1-9547) and by Ester Neuroscience Ltd. Chava Perry, M.D., is the incumbent of a basic research fellowship from the Israel Ministry of Health. The other authors wish to dedicate this manuscript to our co-author, Prof. Amiram Eldor, who died while we were preparing this paper for submission.

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  1. Michael Shapira

    Present address: Department of Genetics, Stanford University School of Medicine, CA, 94305-5120, USA

  2. Amiram Eldor: Deceased

Authors and Affiliations

  1. Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, 91904, Israel

    Chava Perry, Ella H Sklan, Klara Birikh, Michael Shapira & Hermona Soreq

  2. Department of Hematology, The Tel-Aviv Sourasky Medical Center, Tel Aviv and Tel-Aviv University, 64239, Israel

    Chava Perry & Amiram Eldor

  3. Department of Pathology, The Tel-Aviv Sourasky Medical Center, Tel Aviv and Tel-Aviv University, 64239, Israel

    Leonor Trejo

  4. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, 117799, Russia

    Klara Birikh

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Correspondence to Hermona Soreq.

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Perry, C., Sklan, E., Birikh, K. et al. Complex regulation of acetylcholinesterase gene expression in human brain tumors. Oncogene 21, 8428–8441 (2002). https://doi.org/10.1038/sj.onc.1205945

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