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Overexpression of bone morphogenetic protein-6 (BMP-6) in murine epidermis suppresses skin tumor formation by induction of apoptosis and downregulation of fos/jun family members

Oncogene volume 20, pages 7761–7769 (2001)Cite this article

Abstract

Bone morphogenetic protein-6 (BMP-6) is a member of the transforming growth factor-ß superfamily. In murine skin, BMP-6 is highly expressed in postmitotic keratinocytes from day 15.5 p.c. till day 6 p.p. Expression in adult skin remains at very low levels, but pathological conditions such as wounding induce the expression of BMP-6. We demonstrate that tumor promotion by TPA (12-O-tetradecanoylphorbol-13-acetate) also induces expression of BMP-6 in suprabasal keratinocytes. This induction is due to post-transcriptional regulation since the level of BMP-6 mRNA remained unchanged. We performed two-stage skin carcinogenesis experiments with transgenic mice epidermally overexpressing BMP-6. These mice display augmented mitotic indices in normal and TPA-treated epidermis when compared to controls. Despite this hyperproliferation, BMP-6 transgenics showed a delayed development and strong suppression of benign and malignant skin tumor formation. In order to resolve this paradox we determined apoptotic frequencies as well as the expression of constituents of AP-1 (activator protein-1) which is essential for tumor promotion. A higher rate of apoptotic keratinocytes was detectable in transgenic mice versus controls and a downregulation of mRNA for jun/fos family members in transgenic skin after TPA-treatment. Thus expression of BMP-6 augments apoptosis and downregulates the transcription of AP-1 family members thereby establishing tumor resistance.

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References

  • Amendt C, Schirmacher P, Weber H, Blessing M . 1998 Oncogene 17: 25–34

  • Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, Karin M . 1987 Cell 49: 729–739

  • Angel P, Karin M . 1991 Biochim. Biophys. Acta. 1072: 129–157

  • Autzen P, Robson CN, Bjartell A, Malcolm AJ, Johnson MI, Neal DE, Hamdy FC . 1998 Br. J. Cancer 78: 1219–1223

  • Bailleul B, Surani MA, White S, Barton SC, Brown K, Blessing M, Jorcano J, Balmain A . 1990 Cell 62: 697–708

  • Blessing M, Nanney LB, King LE, Hogan BL . 1995 Teratog Carcinog Mutagen 15: 11–21

  • Blessing M, Schirmacher P, Kaiser S . 1996 J. Cell. Biol. 135: 227–239

  • Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE . 1988 J. Cell. Biol. 106: 761–771

  • Brown K, Quintanilla M, Ramsden M, Kerr IB, Young S, Balmain A . 1986 Cell 46: 447–456

  • Choi SE, Choi EY, Kim PH, Kim JH . 1999 Cell Signal 11: 71–76

  • Clement JH, Sanger J, Hoffken K . 1999 Int. J. Cancer 80: 250–256

  • Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, Akhurst RJ . 1996 Cell 86: 531–542

  • Denning MF, Guy SG, Ellerbroek SM, Norvell SM, Kowalczyk AP, Green KJ . 1998 Exp. Cell Res. 239: 50–59

  • DiGiovanni J . 1991 Modification of Tumor Development in Rodents, Vol. 33. Ito N and Sugano H (eds) Karger: Basel pp 192–229

  • DiGiovanni J . 1992 Skin Carcinogenesis in Man and in Experimental Models. Recent Results in Cancer Research, Vol. 54. Grunberger D (ed) Springer-Verlag pp 63–128

  • Dotto GP, Gilman MZ, Maruyama M, Weinberg RA . 1986 EMBO J. 5: 2853–2857

  • Drozdoff V, Wall NA, Pledger WJ . 1994 Proc. Natl. Acad. Sci. USA. 91: 5528–5532

  • Glick AB, Kulkarni AB, Tennenbaum T, Hennings H, Flanders KC, O'Reilly M, Sporn MB, Karlsson S, Yuspa SH . 1993 Proc. Natl. Acad. Sci. USA. 90: 6076–6080

  • Greenhalgh DA, Rothnagel JA, Wang XJ, Quintanilla MI, Orengo CC, Gagne TA, Bundman DS, Longley MA, Fisher C, Roop DR . 1993 Oncogene 8: 2145–2157

  • Greenhalgh DA, Wang XJ, Eckhardt JN, Roop DR . 1995 Cell Growth Differ. 6: 579–586

  • Guo Y, Kyprianou N . 1999 Cancer Res. 59: 1366–1371

  • Hamdy FC, Autzen P, Robinson MC, Horne CH, Neal DE, Robson CN . 1997 Cancer Res. 57: 4427–4431

  • Heikinheimo KA, Laine MA, Ritvos OV, Voutilainen RJ, Hogan BL, Leivo IV, Heikinheimo AK . 1999 Cancer Res. 59: 5815–5821

  • Hennings H, Glick AB, Greenhalgh DA, Morgan DL, Strickland JE, Tennenbaum T, Yuspa SH . 1993 Proc. Soc. Exp. Biol. Med. 202: 1–8

  • Hollnagel A, Oehlmann V, Heymer J, Ruther U, Nordheim A . 1999 J. Biol. Chem. 274: 19838–19845

  • Jonk LJ, Itoh S, Heldin CH, ten Dijke P, Kruijer W . 1998 J. Biol. Chem. 273: 21145–21152

  • Kaiser S, Schirmacher P, Philipp A, Protschka M, Moll I, Nicol K, Blessing M . 1998 J. Invest Dermatol 111: 1145–1152

  • Kennard MD, Kang DC, Montgomery RL, Butler AP . 1995 Mol. Carcinog 12: 14–22

  • Lyons KM, Pelton RW, Hogan BL . 1989 Genes Dev. 3: 1657–1668

  • Massague J, Blain SW, Lo RS . 2000 Cell 103: 295–309

  • Matrisian LM . 1994 Ann. NY Acad. Sci. 732: 42–50

  • Megosh L, Gilmour SK, Rosson D, Soler AP, Blessing M, Sawicki JA, O'Brien TG . 1995 Cancer Res. 55: 4205–4209

  • Merino R, Ganan Y, Macias D, Economides AN, Sampath KT, Hurle JM . 1998 Dev. Biol. 200: 35–45

  • Motyl T, Grzelkowska K, Zimowska W, Skierski J, Wareski P, Ploszaj T, Trzeciak L . 1998 Eur. J. Cell Biol. 75: 367–374

  • Munz B, Smola H, Engelhardt F, Bleuel K, Brauchle M, Lein I, Evans LW, Huylebroeck D, Balling R, Werner S . 1999 EMBO J. 18: 5205–5215

  • Pelton RW, Saxena B, Jones M, Moses HL, Gold LI . 1991 J. Cell. Biol. 115: 1091–1105

  • Potten CS . 1975 Br. J. Dermatol 93: 649–658

  • Potten CS, Hume WJ, Parkinson EK . 1984 Br. J. Dermatol 111: 695–699

  • Raida M, Sarbia M, Clement JH, Adam S, Gabbert HE, Hoffken K . 1999 Int. J. Cancer 83: 38–44

  • Rodriguez-Villanueva J, Greenhalgh D, Wang XJ, Bundman D, Cho S, Delehedde M, Roop D, McDonnell TJ . 1998 Oncogene 16: 853–863

  • Ross R, Kleiz R, Reske-Kunz AB . 1995 PCR Methods Appl. 4: 371–375

  • Rutberg SE, Saez E, Lo S, Jang SI, Markova N, Spiegelman BM, Yuspa SH . 1997 Oncogene 15: 1337–1346

  • Saez E, Rutberg SE, Mueller E, Oppenheim H, Smoluk J, Yuspa SH, Spiegelman BM . 1995 Cell 82: 721–732

  • Sellheyer K, Bickenbach JR, Rothnagel JA, Bundman D, Longley MA, Krieg T, Roche NS, Roberts AB, Roop DR . 1993 Proc. Natl. Acad. Sci. USA. 90: 5237–5241

  • Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, Annunziata N, Doetschman T . 1992 Nature 359: 693–699

  • Tang MK, Leung AK, Kwong WH, Chow PH, Chan JY, Ngo-Muller V, Li M, Lee KK . 2000 Dev. Biol. 218: 89–98

  • Teramoto T, Kiss A, Thorgeirsson SS . 1998 Biochem. Biophys. Res. Commun. 251: 56–60

  • Ueyama T, Kawashima S, Sakoda T, Hirata K, Ohashi Y, Yamochi W, Akita H, Yokoyama M . 1998 J. Mol. Cell. Cardiol. 30: 551–562

  • Wall NA, Blessing M, Wright CV, Hogan BL . 1993 J. Cell. Biol. 120: 493–502

  • Yokouchi Y, Sakiyama J, Kameda T, Iba H, Suzuki A, Ueno N, Kuroiwa A . 1996 Development 122: 3725–3734

  • Young MR, Li JJ, Rincon M, Flavell RA, Sathyanarayana BK, Hunziker R, Colburn N . 1999 Proc. Natl. Acad. Sci. USA 96: 9827–9832

  • Younus J, Gilchrest BA . 1992 J. Cell. Physiol. 152: 232–239

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Acknowledgements

We are indebted to Prof Hommel (Statistics Department) for statistical analysis and to Prof Galle (I. Medical Department) for his constant encouragement. This work was funded by a stipendium of the Deutsche Forschungsgemeinschaft in program ‘Graduiertenkolleg Molekulare und zelluläre Mechanismen der Pathogenese’ to S Wach and a grant from the Boehringer Ingelheim Foundation to M Blessing. We thank K Petmecky for technical assistance, T Schild for technical support in TaqMan-analysis and K-J Kallen for reading the manuscript.

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Authors and Affiliations

  1. I. Medical Department, Section of Pathophysiology, Johannes Gutenberg-University, 55131, Mainz, Germany

    Stefanie Wach, Martina Protschka & Manfred Blessing

  2. Institute of Pathology, University of Cologne, 50931, Cologne, Germany

    Peter Schirmacher

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  1. Stefanie Wach
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Correspondence to Manfred Blessing.

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Wach, S., Schirmacher, P., Protschka, M. et al. Overexpression of bone morphogenetic protein-6 (BMP-6) in murine epidermis suppresses skin tumor formation by induction of apoptosis and downregulation of fos/jun family members. Oncogene 20, 7761–7769 (2001). https://doi.org/10.1038/sj.onc.1204962

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