Abstract
Two long and one truncated isoforms (termed LAP*, LAP, and LIP, respectively) of the transcription factor CCAAT enhancer binding protein beta (C/EBPβ) are expressed from a single intronless Cebpb gene by alternative translation initiation. Isoform expression is sensitive to mammalian target of rapamycin (mTOR)-mediated activation of the translation initiation machinery and relayed through an upstream open reading frame (uORF) on the C/EBPβ mRNA. The truncated C/EBPβ LIP, initiated by high mTOR activity, has been implied in neoplasia, but it was never shown whether endogenous C/EBPβ LIP may function as an oncogene. In this study, we examined spontaneous tumor formation in C/EBPβ knockin mice that constitutively express only the C/EBPβ LIP isoform from its own locus. Our data show that deregulated C/EBPβ LIP predisposes to oncogenesis in many tissues. Gene expression profiling suggests that C/EBPβ LIP supports a pro-tumorigenic microenvironment, resistance to apoptosis, and alteration of cytokine/chemokine expression. The results imply that enhanced translation reinitiation of C/EBPβ LIP promotes tumorigenesis. Accordingly, pharmacological restriction of mTOR function might be a therapeutic option in tumorigenesis that involves enhanced expression of the truncated C/EBPβ LIP isoform.
Key message
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Elevated C/EBPβ LIP promotes cancer in mice.
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C/EBPβ LIP is upregulated in B-NHL.
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Deregulated C/EBPβ LIP alters apoptosis and cytokine/chemokine networks.
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Deregulated C/EBPβ LIP may support a pro-tumorigenic microenvironment.
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Acknowledgments
We thank E. Sterneck for providing the Cebpb ko mouse strain; HP Rahn for help with flow cytometry; the radiology department of the Helios Klinikum for help with X-ray radiation; and C. Becker, J. Bergemann, A.V. Giese, P. Heinrich-Gossen, S. Jaksch, R. Leu, S. Spieckermann, and R. Zarmstorff for technical assistance. We are grateful to F. Rosenbauer and T. Müller for valuable discussions. This work was supported by the Deutsche Krebsgesellschaft (grant no. LEFF200708 to A.L.) and by the German Research Council (grant no. TRR-54 to A.L. and U.L.).
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Bégay, V., Smink, J.J., Loddenkemper, C. et al. Deregulation of the endogenous C/EBPβ LIP isoform predisposes to tumorigenesis. J Mol Med 93, 39–49 (2015). https://doi.org/10.1007/s00109-014-1215-5
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DOI: https://doi.org/10.1007/s00109-014-1215-5