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The role of the transcription factor AP-1 in colitis-associated and β-catenin-dependent intestinal tumorigenesis in mice

Abstract

Chronic inflammation is an important cancer risk factor but the molecular pathways linking inflammation and cancer are incompletely understood. The transcription factor c-Jun/AP-1 (activator protein 1) is involved in inflammatory responses and tumorigenesis and has been proposed as an essential mediator of oncogenic β-catenin signaling in the intestine. Here, we examined the functions of c-Jun in two distinct mouse models of conditional and intestine-specific activation of β-catenin. c-Jun is strongly expressed in the small intestine of mutant mice. However, β-catenin-dependent cell proliferation is surprisingly not affected in mice lacking c-jun in intestinal epithelium, suggesting that c-Jun is not an essential immediate target of β-catenin signaling in the small intestine. To examine the functions of Jun and Fos proteins during inflammation and cancer in the colon, colitis-associated tumors were induced chemically in the respective knockout mice. Tumors were characterized by activated β-catenin and strongly expressed c-Jun and JunB. However, tumorigenesis was not affected by inactivation of c-Jun in either intestinal epithelium or myeloid cells. Moreover, tumorigenesis was not altered in mice lacking junB, junD, c-fos, fra-1 or fra-2, suggesting that inhibition of c-Jun or other single AP-1 proteins is not a determining factor in colitis-associated cancer in mice.

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Acknowledgements

We are very grateful to Drs L Bakiri, A Behrens, R Eferl and O Sansom for critical reading of the manuscript and helpful discussions, Drs S Robine, C Hartmann, M Taketo and O Sansom for providing mutant mice and V Komnenovic and M Grivej for technical assistance with immunohistochemistry. The IMP is funded by Boehringer Ingelheim and this work was also supported by the Austrian Industrial Research Promotion Fund and by a WWTF grant from the city of Vienna. PH and LG were funded by postdoctoral fellowships of the German Research Foundation and EMBO, respectively.

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Correspondence to E F Wagner.

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Hasselblatt, P., Gresh, L., Kudo, H. et al. The role of the transcription factor AP-1 in colitis-associated and β-catenin-dependent intestinal tumorigenesis in mice. Oncogene 27, 6102–6109 (2008). https://doi.org/10.1038/onc.2008.211

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