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

Two long and one truncated isoforms (termed LAP*, LAP, and LIP, respectively) of the transcription factor CCAAT enhancer binding protein beta (C/EBP beta) 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/EBP beta mRNA. The truncated C/EBP beta LIP, initiated by high mTOR activity, has been implied in neoplasia, but it was never shown whether endogenous C/EBP beta LIP may function as an oncogene. In this study, we examined spontaneous tumor formation in C/EBP beta knockin mice that constitutively express only the C/EBP beta LIP isoform from its own locus. Our data show that deregulated C/EBP beta LIP predisposes to oncogenesis in many tissues. Gene expression profiling suggests that C/EBP beta LIP supports a pro-tumorigenic microenvironment, resistance to apoptosis, and alteration of cytokine/chemokine expression. The results imply that enhanced translation reinitiation of C/EBP beta LIP promotes tumorigenesis. Accordingly, pharmacological restriction of mTOR function might be a therapeutic option in tumorigenesis that involves enhanced expression of the truncated C/EBP beta LIP isoform.