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

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/EBPα 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 30 kDa dominant negative C/EBPα isoform, which contributes to loss of C/EBPα function. The molecular basis for this observation remains unknown. In addition to phosphorylation, C/EBPα is modified, post-translationally 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.