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

Abstract

Two long and one truncated isoforms (termed LAP*, LAP, and LIP, respectively) of the transcription factor C/EBPβ are expressed from a single intronless Cebpb gene by alternative translation initiation. Isoform expression is sensitive to mTOR mediated activation of the translation initiation machinery and relayed through an uORF on the C/EBPβ mRNA.The truncated C/EBPβ LIP, initiated by high mTOR activity, has been implied in neoplasia, but it was never shown whether endogenous C/EBPβ LIP may function as an oncogene. In this study we examined spontaneous tumor formation in C/EBPβ knockin mice that constitutively express only the C/EBPβ LIP isoform from its own locus. Our data show that deregulated C/EBPβ LIP predisposes to oncogenesis in many tissues. Gene expression profiling suggests that C/EBPβ LIP supports a pro-tumorigenic microenvironment, resistance to apoptosis, and alteration of cytokine/chemokine expression. The results imply that enhanced translation re-initiation of C/EBPβ LIP promotes tumorigenesis. Accordingly, pharmacological restriction of mTOR function might be a therapeutic option in tumorigenesis that involves enhanced expression of the truncated C/EBPβ LIP isoform.3

The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer

“…In contrast, we observed that CEBPB was associated with greater risk of progression and abrogated any “benefit” of IL6 gene expression. This result agrees with many studies that have shown a role for C/EBPβ – and in particular of its truncated isoform – in the progression of breast cancer 7, 57 . The complexity of cell types within tumors and tumor cell heterogeneity are important aspects of tumor development and progression.…”

New frontiers in translational control of the cancer genome

“…Interestingly, some mRNAs even depend on uORFs for optimal translation. For example, genetic deletion of a uORF in the 5′UTR of the transcription factor CCAAT/enhancer-binding protein-β ( CEBPB ) in mice has revealed that this element is required for physiological in vivo expression of the C/EBPβ liver inhibitory protein (LIP) isoform 76 , which mediates breast cancer cell resistance to the TGFβ cytostatic response 77 and increases tumour susceptibility when overexpressed in mice 78 . Importantly, although these studies demonstrate the potential for uORFs to steer transcript-specific translation in cancer, the vast majority of predicted uORFs remain to be functionally validated.…”

C/EBPβ and C/EBPδ transcription factors: Basic biology and roles in the CNS

“…Interestingly, in vivo expression of LIP in the absence of Full and LAP predisposes to oncogenesis in many tissues (Begay et al 2015). Care must be taken when studying or interpreting reports of LIP expression since a LIP-like isoform can be generated artifactually by proteolysis during extract preparation .…”