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Repression of in vivo growth of Myc/Ras transformed tumor cells by Mad1

Oncogene volume 21, pages 447–459 (2002)Cite this article

Abstract

The Myc/Max/Mad network of transcriptional regulatory proteins plays an essential role in cell proliferation, growth, apoptosis, and differentiation. Whereas Myc proteins affect cell cycle progression positively, Mad proteins are negative regulators of cell proliferation. It has been shown in several in vitro systems that Mad proteins antagonize c-Myc functions. In this report we describe the inhibition of tumor cell outgrowth in vivo by Mad1 expression. Transformed cell lines were generated by co-transfection of c-myc, c-H-ras, and a chimeric mad1ER construct into primary rat embryo cells (MRMad1ER cells). Activation of Mad1 by 4-Hydroxy-Tamoxifen (OHT) resulted in abrogation of telomerase activity, reduced cloning efficiency, and decreased proportion of cells in S phase. Injection of MRMad1ER cells into syngenic rats induced aggressively growing tumors after a short latency period. This tumor growth was inhibited by OHT-treatment of animals, with the extent of inhibition correlating with the amount of OHT injected. No effect of OHT on tumor growth was observed with similarly transformed Myc/Ras cell lines which did not express Mad1ER. These data demonstrate that Mad1 is able to suppress Myc/Ras-mediated transformation under in vivo conditions.

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References

  • Alland L, Muhle R, Hou H, Potes J, Chin L, Schreiber-Agus N, DePinho R . 1997 Nature 387: 49–55

  • Amati B, Frank SR, Donjerkovic D, Taubert S . 2001 Biochim. Biophys. Acta 1471: M135–M145

  • Avilion AA, Piatyszek MA, Gupta J, Shay JW, Bacchetti S, Greider CW . 1996 Cancer Res. 156: 645–650

  • Ayer DE, Eisenman RN . 1993 Genes Dev. 7: 2110–2119

  • Ayer DE, Kretzner L, Eisenman RN . 1993 Cell 72: 211–222

  • Bazarov AV, Adachi S, Li S-F, Mateyak MK, Wie S, Sedivy JM . 2001 Cancer Res. 61: 1178–1180

  • Bejarano MT, Albihn AA, Cornvik T, Brijker SO, Asker C, Osorio LM, Henriksson M . 2000 Exp. Cell Res. 260: 61–72

  • Blackwood E, Eisenman R . 1991 Science 252: 1211–1217

  • Blasco MA, Lee H-W, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW . 1997 Cell 91: 25–34

  • Bouchard C, Dittrich O, Kiermaier A, Dohmann K, Menkel A, Eilers M, Lüscher B . 2001 Genes Dev. 15: 2042–2047

  • Cerni C, Bousset K, Seelos C, Burkhard H, Henriksson M, Lüscher B . 1995 Oncogene 11: 587–596

  • Cerni C, Patocka K, Meneguzzi G . 1990 Virology 177: 427–436

  • Cerni C . 2000 Mut. Res. 462: 31–47

  • Chen J, Willingham T, Margraf LR, Schreiber-Agus N, DePinho RA, Nisen PD . 1995 Nature Med. 1: 638–643

  • Cole MD, McMahon SB . 1999 Oncogene 18: 2916–2924

  • Coller HA, Grandori C, Tamayo P, Colbert T, Lander ES, Eisenman RN, Golub TR . 2000 Proc. Natl. Acad. Sci. USA 97: 3260–3265

  • Cong Y-S, Bacchetti S . 2000 J. Biol. Chem. 275: 35665–35668

  • Cultraro CM, Bino T, Segal S . 1997 Mol. Cell. Biol. 17: 2353–2359

  • DePinho RA, Schreiber-Agus N, Alt FW . 1991 Adv. Cancer Res. 57: 1–46

  • Eilers M . 1999 Mol. Cells 9: 1–6

  • Facchini LM, Penn LZ . 1998 FASEB J. 12: 2149–2154

  • Falcetti ML, Falcone G, D'Ambrosio E, Verna R, Alema S, Levi A . 1999 Oncogene 18: 1515–1519

  • Foley KP, McArthur GA, Quéva C, Hurlin PJ, Soriano P, Eisenman RN . 1998 EMBO J. 17: 774–785

  • Gehring S, Rottmann S, Menkel AR, Mertsching J, Krippner-Heidenreich A, Lüscher B . 2000 J. Biol. Chem. 275: 10413–10420

  • Good DJ, Polverini PJ, Rastinejad F, LeBeau MM, Lemons RS, Frazier WA, Bouck NP . 1990 Proc. Natl. Acad. Sci. USA 87: 6624–6628

  • Gorman C, Padmanabhan R, Howard BH . 1983 Science 221: 551–553

  • Grandori C, Cowley SM, James LP, Eisenman RN . 2000 Annu. Rev. Cell. Dev. Biol. 16: 653–699

  • Greenberg RA, O'Hagan RC, Deng H, Yiao Q, Hann SR, Adams RR, Lichtsteiner S, Chin L, Morin GB, DePinho RA . 1999 Oncogene 18: 1219–1226

  • Gundimeda U, Chen ZH, Gopalakrishna R . 1996 J. Biol. Chem. 23: 13504–13514

  • Günes C, Lichtsteiner S, Vasserot AP, Englert C . 2000 Cancer Res. 60: 2116–2121

  • Guo QM, Malek RL, Kim S, Chiao C, He M, Ruffy M, Sanka K, Lee NH, Dang CV, Liu ET . 2001 Cancer Res. 60: 5922–5928

  • Han S, Park K, Kim H-Y, Lee M-S, Kim Y-D, Yuh YJ, Kim SR, Suh HS . 2000 Cancer 88: 1623–1632

  • Hassig C, Fleischer T, Billin AN, Schreiber SL, Ayer DE . 1997 Cell 89: 341–347

  • Heinzel T, Lavinsky RM, Muller T-M, Söderström M, Laherty CD, Torchia J, Yang W-M, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG . 1997 Nature 387: 43–48

  • Henriksson M, Lüscher B . 1996 Adv. Cancer Res. 68: 109–182

  • Hurlin PJ, Quéva C, Koskinen PJ, Steingrimsson E, Ayer DE, Copeland NG, Jenkins NA, Eisenman RN . 1995 EMBO J. 14: 5646–5659

  • Hurlin P, Quéva C, Eisenman RN . 1997 Genes Dev. 11: 44–58

  • Hurlin PJ, Steingrimsson E, Copeland NG, Jenkins NA, Eisenman RN . 1999 EMBO J. 18: 7019–7028

  • Johnson LA, Prober DA, Edgar BA, Eisenman RN, Gallant P . 1999 Cell 98: 779–790

  • Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PLC, Coviello GM, Wright WE, Wienrich SL, Shay JW . 1994 Science 266: 2011–2015

  • Koskinen PJ, Ayer DE, Eisenman RN . 1995 Cell Growth Differ. 6: 623–629

  • Laherty CD, Yang W-M, Sun J-M, Davie JR, Seto E, Eisenman RN . 1997 Cell 89: 349–356

  • Lahoz EG, Xu L, Schreiber-Agus N, DePinho RA . 1994 Proc. Natl. Acad. Sci. USA 91: 5503–5507

  • Land H, Parada LF, Weinberg RA . 1983 Nature 304: 596–602

  • Larcher F, Robles AI, Duran H, Murillas R, Quintanilla M, Cano A, Conti CJ, Jorcano JL . 1996 Cancer Res. 56: 5391–5396

  • Larsson LG, Pettersson M, Oberg F, Nilsson K, Lüscher B . 1994 Oncogene 9: 1247–1252

  • Lee TH, Chuang LY, Hung WC . 2000 Oncogene 19: 3766–3773

  • Lüscher B . 2001 Gene 277: 1–14

  • Lüscher B, Larsson L-G . 1999 Oncogene 8: 2954–2965

  • McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD, Cole MD . 1998 Cell 94: 363–374

  • McMahon SB, Wood MA, Cole MD . 2000 Mol. Cell. Biol. 20: 556–562

  • Meroni G, Reymond A, Alcalay M, Borsani G, Tanigami A, Tonlorenzi R, Nigro CL, Messali S, Zollo M, Ledbetter DH, Brent R, Ballabio A, Carrozzo R . 1997 EMBO J. 16: 2892–2906

  • Ngo CV, Gee M, Akhtar N, Yu D, Volpert O, Auerbach R, Thomas-Tikhonenko A . 2000 Cell Growth Differ. 11: 201–210

  • Oh S, Song Y-H, Yim J, Kim TK . 2000 Oncogene 19: 1485–1490

  • O'Hagan RC, Schreiber-Agus N, Chen K, David G, Engelmann JA, Schwab R, Alland L, Thomson C, Ronning DR, Sacchettini JC, Meltzer P, DePinho RA . 2000 Nature Genet. 24: 113–119

  • Prasad GL, Masuelli L, Raj MH, Harindranath N . 1999 Oncogene 18: 2027–2031

  • Pulverer B, Sommer A, McArthur GA, Eisenman RN, Luscher B . 2000 J. Cell Physiol. 183: 399–410

  • Quéva C, Hurlin PJ, Foley KP, Eisenmann RN . 1998 Oncogene 16: 967–977

  • Quéva C, McArthur GA, Ramos LS, Eisenman RN . 1999 Cell Growth Differ. 10: 785–796

  • Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS . 1995 Cancer Res. 55: 4575–4580

  • Roussel MF, Ashmun RA, Sherr CJ, Eisenman RN, Ayer DE . 1996 Mol. Cell. Biol. 16: 2796–2801

  • Roy B, Reisman D . 1995 Cell Biol. Intern. 19: 307–313

  • Shay JW, Bacchetti S . 1997 Eur. J. Cancer 33: 787–791

  • Sommer A, Hilfenhaus S, Menkel A, Kremmer E, Seiser C, Loidl P, Lüscher B . 1997 Curr. Biol. 7: 357–365

  • Treon SP, Teoh G, Urashima M, Ogata A, Chauhan D, Webb IJ, Anderson KC . 1998 Blood 92: 1749–1757

  • Ulaner GA, Hu J-F, Vu TH, Giudice LC, Hoffman AR . 1998 Cancer Res. 58: 4168–4172

  • Västrik I, Kaipainen A, Penttilä T-L, Lymboussakis A, Alitalo R, Parvinen M, Alitalo K . 1995 J. Cell. Biol. 128: 1197–1208

  • Wang J, Xie LY, Allan S, Beach D, Hannon GJ . 1998 Genes Dev. 12: 1769–1774

  • Wu K-J, Grandori C, Amacker M, Simon-Vermont N, Polack A, Lingner J, Dalla-Favera R . 1999 Nature Gen. 21: 220–224

  • Xu D, Popov N, Hou M, Wang Q, Björkholm M, Gruber A, Menkel AR, Henriksson M . 2001 Proc. Natl. Acad. Sci. USA 98: 3826–3831

  • Zervos A, Gyuris J, Brent R . 1993 Cell 72: 223–232

  • Zhu J, Wang H, Bishop M, Blackburn EH . 1999 Proc. Natl. Acad. Sci. USA 96: 3723–3728

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Acknowledgements

We thank G Krupitza for critical reading of the manuscript, D Ayer, RN Eisenman, L Kretzner, and J Lüscher-Firzlaff for plasmids, M Sjöberg for the ER antibody, and K Andersson, M Hajek, and C Schreiner for excellent technical assistance. This work was supported by the Institute of Cancer Research of the University of Vienna (CC), the Deutsche Forschungsgemeinschaft (BL), and the Swedish Cancer Society (MH).

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Authors and Affiliations

  1. Institute of Cancer Research, University of Vienna, Borschkegasse 8a, Wien, A-1090, Austria

    Christa Cerni, Barbara Skrzypek, Soleman Sasgary & Gerlinde Schmidt

  2. Microbiology and Tumor Biology Center, Karolinska Instituet, Box 280, Stockholm, SE-171 77, Sweden

    Nikita Popov & Marie Henriksson

  3. Department of Plant Biology, Uppsala Genetic Center, Box 7080, Swedish University of Agricultural Sciences, Uppsala, SE-750 07, Sweden

    Lars-Gunnar Larsson

  4. Abteilung für Biochemie und Molekularbiologie, Institut für Biochemie, RWTH, Pauwelstrasse 30, Aachen, D-52074, Germany

    Bernhard Lüscher

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  1. Christa Cerni
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Correspondence to Christa Cerni or Marie Henriksson.

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Cerni, C., Skrzypek, B., Popov, N. et al. Repression of in vivo growth of Myc/Ras transformed tumor cells by Mad1. Oncogene 21, 447–459 (2002). https://doi.org/10.1038/sj.onc.1205107

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