Repressive effect of Sp1 on the C/EBPα gene promoter:: Role in adipocyte differentiation

Expression of C/EBP alpha is required for differentiation of 3T3-L1 preadipocytes into adipocytes. Previous investigations indicated that transcription of the C/EBP alpha gene is sequentially activated during differentiation, initially by C/EBP beta and C/EBP delta and later by C/EBP alpha (autoactivation). These events are mediated by a C/EBP regulatory element in the promoter of the C/EBP alpha gene. This article presents evidence that members of the Sp family, notably Spl, act repressively on the C/EBP alpha promoter prior to the induction of differentiation. Sp1 was shown to bind to a GC box at the 5' end of the C/EBP regulatory element in the C/EBP alpha promoter and, in so doing, to competitively prevent binding to and transactivation of the promoter by the C/EBPs. One of the differentiation inducers methylisobutylxanthine (a cAMP phosphodiesterase inhibitor) or Forskolin, both of which increase the cellular cAMP level, causes down-regulation of Sp1. This decrease in Sp1 level early in the differentiation program appears to facilitate access of C/EBP beta and/or C/EBP delta to the C/EBP regulatory element and, thereby, derepression of the C/EBP alpha gene.