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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. and Smink, J.J. and Loddenkemper, C. and Zimmermann, K. and Rudolph, C. and Scheller, M. and Steinemann, D. and Leser, U. and Schlegelberger, B. and 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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