Sequential repression and activation of the CCAAT enhancer-binding protein-α (C/EBPα) gene during adipogenesis

CCAAT enhancer-binding protein-α (C/EBPα) functions as a pleiotropic transcriptional activator of adipocyte genes during adipogenesis. Nuclear factor C/EBP undifferentiated protein (CUP), an isoform of activator protein-2α (AP-2α), binds to repressive elements in the C/EBPα gene promoter, silencing the gene until late in the differentiation program. The CUP regulatory element overlaps a Sp (GT-box) element in the promoter to which Sp3 (or Sp1) can bind. Binding by Sp3 or Sp1 and CUP/AP2-α is mutually exclusive. Sp3 is a strong transcriptional activator of the C/EBPα gene promoter in 3T3-L1 preadipocytes and Schneider cells, this activation being repressed by CUP/AP-2α. Sp3 is expressed throughout differentiation, whereas CUP/AP-2α, which is expressed only by preadipocytes, is down-regulated during differentiation coincident with transcription of the C/EBPα gene. Thus, CUP/AP-2α delays access of Sp3 to the Sp regulatory element, preventing premature expression of C/EBPα and thereby interference by C/EBPα (which is antimitotic) with mitotic clonal expansion, an essential early event in the differentiation program.