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

CCAAT enhancer-binding protein-alpha (C/EBP alpha) functions as a pleiotrop ic transcriptional activator of adipocyte genes during adipogenesis. Nuclea r factor C/EBP undifferentiated protein (CUP), an isoform of activator prot ein-2 alpha (AP-2 alpha), binds to repressive elements in the C/EBP alpha g ene 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-alpha is mutually exclusive. Sp3 is a strong transcriptional activator of the C/EBP alpha gene promoter in 3T3-L1 preadipocytes and Schneider cells, this activ ation being repressed by CUP/AP-2 alpha. Sp3 is expressed throughout differ entiation, whereas CUP/AP-2 alpha. which is expressed only by preadipocytes . is down-regulated during differentiation coincident with transcription of the C/EBP alpha gene. Thus. CUP/AP-2 alpha delays access of Sp3 to the Sp regulatory element. preventing premature expression of C/EBP alpha and ther eby interference by C/EBP alpha (which is antimitotic) with mitotic clonal expansion, an essential early event in the differentiation program.