Transcription Factor Interactions: Selectors of Positive or Negative Regulation from a Single DNA Element

• Published in: Science (American Association for the Advancement of Science) 1990-09, Vol.249 (4974), p.1266-1272
• Main Authors: Diamond, Marc I., Miner, Jeffrey N., Yoshinaga, Steven K., Yamamoto, Keith R.
• Format: Article
• Language: English
• Subjects: 560300 - Chemicals Metabolism & Toxicology; ADRENAL HORMONES; Analysis; ANIMALS; Base Sequence; BIOCHEMICAL REACTION KINETICS; CARCINOGENS; Cells; CORTICOSTEROIDS; Cross-Linking Reagents; DNA; DNA-Binding Proteins - physiology; ESTERS; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; GENE REGULATION; GENES; Genetic regulation; Genetic transcription; Glucocorticoid receptors; GLUCOCORTICOIDS; Glucocorticoids - physiology; Glycoproteins - genetics; HeLa Cells; Hormones; Humans; HYDROXY COMPOUNDS; Intercellular Signaling Peptides and Proteins; KETONES; KINETICS; MAMMALS; MATHEMATICAL MODELS; MEMBRANE PROTEINS; MICE; Molecular Sequence Data; NUCLEIC ACIDS; NUCLEOPROTEINS; Nucleotide sequence; ORGANIC COMPOUNDS; PHORBOL ESTERS; Plasmids; PREGNANES; PROTEINS; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT; REACTION KINETICS; RECEPTORS; Receptors, Glucocorticoid - metabolism; Regulation; Regulatory Sequences, Nucleic Acid - genetics; Repression; RODENTS; STEROIDS; Tetradecanoylphorbol Acetate - pharmacology; Transcription (Genetics); TRANSCRIPTION FACTORS; Transcription Factors - physiology; Transcription, Genetic - drug effects; VERTEBRATES
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.2119054

The mechanism by which a single factor evokes opposite regulatory effects from a specific DNA sequence is not well understood. In this study, a 25-base pair element that resides upstream of the mouse proliferin gene was examined; it conferred on linked promoters either positive or negative glucocorticoid regulation, depending upon physiological context. This sequence, denoted a "composite" glucocorticoid response element (GRE), was bound selectively in vitro both by the glucocorticoid receptor and by c-Jun and c-Fos, components of the phorbol ester-activated AP-1 transcription factor. Indeed, c-Jun and c-Fos served as selectors of hormone responsiveness: the composite GRE was inactive in the absence of c-Jun, whereas it conferred a positive glucocorticoid effect in the presence of c-Jun, and a negative glucocorticoid effect in the presence of c-Jun and relatively high levels of c-Fos. The receptor also interacted selectively with c-Jun in vitro. A general model for composite GRE action is proposed that invokes both DNA binding and protein-protein interactions by receptor and nonreceptor factors.