COMBINATORIAL INTERACTIONS BETWEEN AP-1 AND ETS DOMAIN PROTEINS CONTRIBUTE TO THE DEVELOPMENTAL REGULATION OF THE MACROPHAGE SCAVENGER RECEPTOR GENE

Macrophage development is regulated by a complex set of hormone-like m olecules and cell adhesion events that control the growth and differen tiation of progenitor cells. The macrophage scavenger receptor (SR) ge ne becomes markedly upregulated during the final stages of monocyte-to -macrophage differentiation and provides a model for the identificatio n and characterization of transcription factors that control this proc ess. In this report, we have identified three genomic regulatory eleme nts that are required for transactivation of the SR gene in the THP-1 monocytic leukemia cell line following induction of macrophage differe ntiation by tetradecanoyl phorbol acetate. Each of these regulatory el ements contains a near-consensus binding site for members of the AP-1 gene family, while the two most quantitatively important elements also contain juxtaposed binding sites for ets domain transcription factors . We demonstrate that tetradecanoyl phorbol acetate treatment results in a marked and prolonged increase in AP-I binding activity on these e lements, which can be accounted for almost entirely by c-jun and junB. These proteins in turn form ternary complexes with additional factors that bind to the adjacent ets recognition motifs. Several indirect li nes of evidence indicate that ets2 represents a component of this tern ary complex. The combined expression of c-jun, ets2, and a constitutiv e form of ras result in synergistic increases in transcription from pr omoters containing the SR regulatory elements. These observations sugg est that SR gene expression is regulated via a signal transduction pat hway involving ras, AP-1, and ets domain proteins and imply that at le ast some of the signalling components involved in ras-dependent growth are also utilized to promote the expression of genes involved in term inal differentiation.