Negative regulation of serum-responsive enhancer elements

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Abstract
TRANSCRIPTION of the c-fos proto-oncogene and the cytoskeletal actin genes is induced within minutes of the addition of serum growth factors in a variety of cell types1,2. Inhibitors of protein synthesis such as cycloheximide have been shown to dramatically potentiate the transcriptional response, an effect termed 'superinduction' (refs 1–3). Although the stimulatory effect of serum has been shown to be transmitted through a cis-acting enhancer sequence termed a serum response element (SRE)4,5, the sequence element(s) responsible for mediating the effect of cycloheximide has not been identified. We now report that a synthetic copy of the c-fos SRE is sufficient to confer cycloheximide-dependent inducibility upon a heterologous promoter. This does not require the presence of serum, but several mutations in the SRE that impair serum-inducibility also impair cycloheximide-inducibility. These results imply that serum-responsive enhancer elements are negatively regulated by one or more labile proteins and that both positive and negative regulators of enhancer activity require a functional 'CArG box', a sequence domain previously implicated in muscle-specific transcription6,7.