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Epigenetic mechanisms affect mutant p53 transgene expression in WAP-mutp53 transgenic mice

Oncogene volume 24, pages 4645–4659 (2005)Cite this article

Abstract

We describe the construction and phenotypic characterization of 23 whey acidic protein (WAP)-mutp53 transgenic mouse lines. The mutp53-expressing lines showed a mosaic expression pattern for the transgenes, leading to a heterogeneous yet mouse line-specific expression pattern for mutp53 upon induction. Only few lines were obtained, in which the majority of the induced mammary epithelial cells expressed the mutp53 transgene, most of the transgenic lines did not express mutp53, or expressed the transgene in less than 2% of the induced mammary epithelial cells. Hormone requirements for mutp53 transgene expression from the WAP-promoter differed in high and low expressing lines, being low in high expressing lines, and even lower in multiparous mutp53 mice, where persistent expression of the transgene occurred. Repeated induction of mutp53 expression through repeated parturition resulted in the formation of expanding mutp53-expressing foci within the mammary alveolar epithelium. The data suggest that epigenetic mechanisms play a role in modulating the expression of the mutp53 transgene. To support this idea, we crossed a nonexpressing WAP-mutp53 line with a strongly SV40 T-antigen-expressing WAP-T mouse line. In the bitransgenic mice, T-antigen-induced chromatin remodeling led to re-expression of epigenetically silenced mutp53 transgene(s). In these mice, mutp53 expression was much more variable compared to SV40 T-antigen expression, and seemed to depend on the coexpression of SV40 T-antigen. Mutp53 expression in this system thus resembles the situation in many human tumors, where one can observe a heterogeneous expression of mutp53, despite a homogeneous distribution of the p53 mutation in the tumor cells.

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Acknowledgements

We thank Dr M Bösl, Zentrum für Molekulare Neurobiologie der Universität Hamburg (ZMNH) for help with the microinjection experiments, Ms A Diesterbeck and Ms K Heigl for expert technical help, and Ms M Hintz-Malchow for editing the manuscript. This research was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 545), from the Erich and Gertrud Roggenbuck-Stiftung, the EC (QLG1-1999-00273), and by EC FP6 funding. The Heinrich-Pette-Institut is financially supported by Freie und Hansestadt Hamburg and Ministerium für Gesundheit und Soziale Sicherung. This publication reflects the author's views and not necessarily those of the EC. The Community is not liable for any use that may be made of the information contained herein. The work described herein is part of the Ph.D. thesis by CH.

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  1. Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Martinistrasse 52, D-20251, Hamburg, Germany

    Frauke Krepulat, Jürgen Löhler, Christina Heinlein, Andrea Hermannstädter, Genrich V Tolstonog & Wolfgang Deppert

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  1. Frauke Krepulat
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Correspondence to Wolfgang Deppert.

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Krepulat, F., Löhler, J., Heinlein, C. et al. Epigenetic mechanisms affect mutant p53 transgene expression in WAP-mutp53 transgenic mice. Oncogene 24, 4645–4659 (2005). https://doi.org/10.1038/sj.onc.1208557

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