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The glucocorticoid receptor synergizes with Jun homodimers to activate AP-1-regulated promoters lacking GR binding
Abstract:
Jun/Fos (AP-1) and steroid hormone receptors (SHR) are distinct families of transcription factors that convert extracellular signals into long-term genetic responses. Despite clear differences in their modes of activation and DNA binding specificities, a regulatory cross-talk between AP-1 and SHR such as the glucocorticoid receptor (GR), has been established. Here, we show that the hormone-activated GR negatively or positively modulates the expression of AP-1-dependent genes, depending on the subunits of the dimeric AP-1 complex. This type of regulation does not depend on the presence of a GR binding site in the promoter and is mediated through the DNA binding domain of Jun. Since individual subunits of AP-1 exhibit small differences in sequence specificity, specific subsets of AP-1-dependent genes may be regulated by steroid hormones in different directions.
Insights
Steroid hormones, like glucocorticoid receptors (GR), can control gene expression by interacting with Jun/Fos (AP-1) transcription factors. This regulation depends on specific AP-1 subunits and involves the Jun DNA binding domain.
Area of Science:
- Molecular Biology
- Genetics
- Cell Signaling
Background:
- Jun/Fos (AP-1) and steroid hormone receptors (SHR) are critical transcription factor families mediating cellular responses.
- While distinct, cross-talk between AP-1 and SHR, specifically the glucocorticoid receptor (GR), is known.
- Understanding these interactions is key to deciphering gene regulation pathways.
Purpose of the Study:
- To investigate the regulatory cross-talk between the hormone-activated glucocorticoid receptor (GR) and the Jun/Fos (AP-1) complex.
- To determine how GR modulates the expression of AP-1-dependent genes.
- To identify the specific domains of AP-1 involved in this interaction.
Main Methods:
- Analysis of AP-1-dependent gene expression in the presence of hormone-activated GR.
- Investigating the role of different AP-1 subunits in GR-mediated regulation.
- Mapping the GR interaction domain within the AP-1 complex, focusing on the DNA binding domain of Jun.
Main Results:
- Hormone-activated GR differentially modulates AP-1-dependent gene expression, acting as a negative or positive regulator.
- The direction of modulation is dependent on the specific subunits forming the AP-1 dimer.
- Regulation occurs independently of a direct GR binding site and is mediated by the Jun DNA binding domain.
Conclusions:
- Steroid hormones, via GR, exert complex control over AP-1 activity.
- The specific composition of AP-1 dimers dictates the outcome of GR interaction.
- This provides a mechanism for fine-tuning gene expression in response to hormonal signals, potentially affecting distinct gene subsets.