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 molecules and cell adhesion events that control the growth and differentiation of progenitor cells. The macrophage scavenger receptor (SR) gene becomes markedly upregulated during the final stages of monocyte-to-macrophage differentiation and provides a model for the identification and characterization of transcription factors that control this process. In this report, we have identified three genomic regulatory elements that are required for transactivation of the SR gene in the THP-1 monocytic leukemia cell line following induction of macrophage differentiation by tetradecanoyl phorbol acetate. Each of these regulatory elements 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-1 binding activity on these elements, 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 lines of evidence indicate that ets2 represents a component of this ternary complex. The combined expression of c-jun, ets2, and a constitutive form of ras result in synergistic increases in transcription from promoters containing the SR regulatory elements. These observations suggest that SR gene expression is regulated via a signal transduction pathway involving ras, AP-1, and ets domain proteins and imply that at least some of the signalling components involved in ras-dependent growth are also utilized to promote the expression of genes involved in terminal differentiation.
Wu
H
H
Division of Cellular and Molecular Medicine, University of California, San Diego, La Jolla 92093-0656.
Moulton
K
K
Horvai
A
A
Parik
S
S
Glass
C K
CK
D001483:Base Sequence; D002467:Cell Nucleus / Q000502:physiology; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D016758:Genes, jun; D006801:Humans; D046911:Macromolecular Substances; D008264:Macrophages / Q000502:physiology*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000502:physiology*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D011994:Recombinant Proteins; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins; D051122:Scavenger Receptors, Class B; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C107465:ERF protein, human; C494069:ETS2 protein, human; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D015534:Trans-Activators; D014157:Transcription Factors; D013755:Tetradecanoylphorbol Acetate