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

TLDR

The mechanism by which a single factor evokes opposite regulatory effects from a specific DNA sequence is not well understood. The study proposes a general model for composite GRE action that involves DNA binding and protein‑protein interactions between receptor and non‑receptor factors. The authors examined a 25‑bp upstream element of the mouse proliferin gene that confers either positive or negative glucocorticoid regulation on linked promoters depending on physiological context, and proposed that DNA binding and protein‑protein interactions mediate this effect. The composite GRE binds glucocorticoid receptor and AP‑1 components c‑Jun and c‑Fos; c‑Jun alone activates glucocorticoid response, while c‑Jun plus high c‑Fos converts it to a negative response, and the receptor also interacts selectively with c‑Jun in vitro.

Abstract

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.