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Deregulation of the endogenous C/EBPβ LIP isoform predisposes to tumorigenesis

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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
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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