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| Item Type: | Article |
|---|---|
| Title: | Deregulation of the endogenous C/EBPβ LIP isoform predisposes to tumorigenesis |
| Creators Name: | Bégay, V., Smink, J.J., Loddenkemper, C., Zimmermann, K., Rudolph, C., Scheller, M., Steinemann, D., Leser, U., Schlegelberger, B., Stein, H. and Leutz, A. |
| Abstract: | Two long and one truncated isoforms (termed LAP*, LAP, and LIP, respectively) of the transcription factor CCAAT enhancer binding protein beta (C/EBPbeta) 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/EBPbeta mRNA. The truncated C/EBPbeta LIP, initiated by high mTOR activity, has been implied in neoplasia, but it was never shown whether endogenous C/EBPbeta LIP may function as an oncogene. In this study, we examined spontaneous tumor formation in C/EBPbeta knockin mice that constitutively express only the C/EBPbeta LIP isoform from its own locus. Our data show that deregulated C/EBPbeta LIP predisposes to oncogenesis in many tissues. Gene expression profiling suggests that C/EBPbeta LIP supports a pro-tumorigenic microenvironment, resistance to apoptosis, and alteration of cytokine/chemokine expression. The results imply that enhanced translation reinitiation of C/EBPbeta LIP promotes tumorigenesis. Accordingly, pharmacological restriction of mTOR function might be a therapeutic option in tumorigenesis that involves enhanced expression of the truncated C/EBPbeta LIP isoform. KEY MESSAGE: Elevated C/EBPbeta LIP promotes cancer in mice. C/EBPbeta LIP is upregulated in B-NHL. Deregulated C/EBPbeta LIP alters apoptosis and cytokine/chemokine networks. Deregulated C/EBPbeta LIP may support a pro-tumorigenic microenvironment. |
| Keywords: | Tumorigenesis, Lymphomagenesis, Translational Control, Tumor-Stroma Interaction, Animals, Mice |
| Source: | Journal of Molecular Medicine |
| ISSN: | 0946-2716 |
| Publisher: | Springer |
| Volume: | 93 |
| Number: | 1 |
| Page Range: | 39-49 |
| Date: | January 2015 |
| Official Publication: | https://doi.org/10.1007/s00109-014-1215-5 |
| PubMed: | View item in PubMed |
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