The many faces of C/EBPδ and their relevance for inflammation and cancer

Abstract

The CCAAT/enhancer binding protein delta (CEBPD, C/EBPδ) is a transcription factor that modulates many biological processes including cell differentiation, motility, growth arrest, proliferation, and cell death. The diversity of C/EBPδ's functions depends in part on the cell type and cellular context and can have opposing outcomes. For example, C/EBPδ promotes inflammatory signaling, but it can also inhibit pro-inflammatory pathways, and in a mouse model of mammary tumorigenesis, C/EBPδ reduces tumor incidence but promotes tumor metastasis. This review highlights the multifaceted nature of C/EBPδ's functions, with an emphasis on pathways that are relevant for cancer and inflammation, and illustrates how C/EBPδ emerged from the shadow of its family members as a fascinating "jack of all trades." Our current knowledge on C/EBPδ indicates that, rather than being essential for a specific cellular process, C/EBPδ helps to interpret a variety of cues in a cell-type and context-dependent manner, to adjust cellular functions to specific situations. Therefore, insights into the roles and mechanisms of C/EBPδ signaling can lead to a better understanding of how the integration of different signaling pathways dictates normal and pathological cell functions and physiology.

Keywords: C/EBP; cancer.; cell signaling; inflammation; transcription factor.

Fig 1

Schematic of the C/EBPδ protein, and mapped modifications and interactions. Only interactors that have been mapped to a sub-domain of C/EBPδ and whose interactions were confirmed at the level of endogenous proteins have been included in this Figure: SIAH2 , FBXW7 , FANCD2 , IPO4 . Amino acids (aa) that are important for protein modifications are indicated: ^#phosphorylation by GSK-3β; *K120 is necessary for acetylation and sumoylation and for ubiquitination by SIAH2 but not by SCF^FBXW7 . K120 was not confirmed as the acceptor site for these modifications. Transactivation Domain: aa 41-108 , Basic Region/Leucine Zipper: aa 195-222/226-254 .

Fig 2

Model for the differential effects of C/EBPδ on epithelial tumor progression. C/EBPδ may function as a tumor suppressor at the early stages of tumor development, because of its role in promoting growth arrest, cell death, differentiation, DNA repair, genomic stability, and the innate immune response. However, by supporting HIF-1 activity and hypoxia adaptation and by amplifying inflammatory signaling, C/EBPδ promotes tumor progression.