Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBPα)

Abstract

CCAAT enhancer binding protein alpha (C/EBPα) is the founding member of a family of basic region/leucine zipper (bzip) transcription factors and is a master regulator of granulopoiesis. It is expressed at high levels throughout myeloid differentiation and binds to the promoters of multiple myeloid-specific genes at different stages of myeloid maturation. Profound hematopoietic abnormalities occur in mice nullizygous for C/EBPα̤ including a selective early block in the differentiation of granulocytes. Mutations in C/EBPα are present in a subset of patients with AML presenting with a normal karyotype. These mutations can result in the expression of a 30kD dominant negative C/EBPα isoform, which contributes to loss of C/EBPα function. The molecular basis for this observation remains unknown. In addition to phoshorylation, C/EBPα is modified, posttranslationally by a small ubiquitin-related modifier (SUMO) at a lysine residue (K159), which lies within the growth inhibitory region of the C/EBPα protein. Sumoylation at K159 in the C/EBPα protein prevents association of the SWI/SNF chromatin remodeling complex with C/EBPα, thereby hampering transactivation. In this review, the functional implications of post-translational modification, particularly sumoylation, of C/EBPα in normal granulopoiesis and leukemia are considered.

CCAAT/Enhancer-Binding Protein α Negatively Regulates IFN-γ Expression in T Cells

“…C/EBP family proteins share highly homologous C-terminal dimerization (leucine zipper) domains and DNA binding [basic region (BR)] motifs but differ in their N-terminal transactivation domains and bind DNA either as homo- or heterodimers (21). C/EBPα has been reported to play critical roles in lineage-specific gene regulation in several cell types during hepatic, adipogenic, granulocytic, skin, lung and placenta development (22).…”

CCAAT/Enhancer-binding Protein α (C/EBPα) Is Critical for Interleukin-4 Expression in Response to FcϵRI Receptor Cross-linking

“…4B). The bZIP domain can be further divided into the DNA binding domain and the leucine zipper domain, which is needed for interaction with other transcription factors, such as PU.1, GATA1, RUNX-1, and p21 waf1/cip1 (30). We showed that mutation in Arg-297, Lys-298, and Arg-300 (collectively, these mutants are called BR3 (31)) eliminated C/EBP␣-driven transcription activity, whereas deletion of the leucine zipper domain only reduced C/EBP␣-driven transcription activity by half.…”

“…Post-translational modifications of C/EBP␣ often occur as the result of signaling activation and have been shown to regulate C/EBP␣ functions (30). Timchenko and co-workers (35) demonstrated that PI3K signaling activated a phosphatase, pp2a, which in turn dephosphorylated C/EBP␣ at Ser-193.…”

The emerging role of C/EBPs in glucocorticoid signaling: lessons from the lung

“…Post-transcriptional modifications such as phosphorylations, SUMOylations, and acetylations have been shown to affect C/EBPb activity (Ramji & Foka 2002, Berberich-Siebelt et al 2006, Cesena et al 2008, Khanna-Gupta 2008. For instance, EGF simulation in vitro has been shown to repress transcription of COX2 via sumoylation of C/EBPb (Wang et al 2008), as opposed to the other documented role of C/EBPb in promoting COX2 transcription (Hsu et al 2010).…”