Unknown,Transcriptomics,Genomics,Proteomics

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Deregulation of the endogenous C/EBPM-NM-2 LIP isoform predisposes to tumorigenesis


ABSTRACT: Two long and one truncated isoforms (termed LAP*, LAP, and LIP, respectively) of the transcription factor CCAAT enhancer binding protein beta (C/EBPM-NM-2) 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/EBPM-NM-2 mRNA. The truncated C/EBPM-NM-2 LIP, initiated by high mTOR activity, has been implied in neoplasia, but it was never shown whether endogenous C/EBPM-NM-2 LIP may function as an oncogene. In this study, we examined spontaneous tumor formation in C/EBPM-NM-2 knockin mice that constitutively express only the C/EBPM-NM-2 LIP isoform from its own locus. Our data show that deregulated C/EBPM-NM-2 LIP predisposes to oncogenesis in many tissues. Gene expression profiling suggests that C/EBPM-NM-2 LIP supports a protumorigenic microenvironment, resistance to apoptosis, and alteration of cytokine/chemokine expression. The results imply that enhanced translation reinitiation of C/ EBPM-NM-2 LIP promotes tumorigenesis. Accordingly, pharmacological restriction of mTOR function might be a therapeutic option in tumorigenesis that involves enhanced expression of the truncated C/EBPM-NM-2 LIP isoform. A cohort of C/EBPb LIP heterozygous (+/L) and wild type (+/+) mice were kept over 25 months and animals showing palpable lymphoma were sacrificed. The lymphoma developed spontaneously. For each genotype, 5 lymphoma were used for RNA preparation and gene expression profiling analysis.

ORGANISM(S): Mus musculus

SUBMITTER: Valerie Begay 

PROVIDER: E-GEOD-53770 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Bégay Valérie V   Smink Jeske J JJ   Loddenkemper Christoph C   Zimmermann Karin K   Rudolph Cornelia C   Scheller Marina M   Steinemann Doris D   Leser Ulf U   Schlegelberger Brigitte B   Stein Harald H   Leutz Achim A  

Journal of molecular medicine (Berlin, Germany) 20141118 1


<h4>Unlabelled</h4>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, initi  ...[more]

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