Cross-talk between glucocorticoid receptor and AP-1

Area of Science:

• Molecular Biology
• Endocrinology
• Immunology

Background:

• Transcription factor cross-talk, particularly between glucocorticoid receptor (GR) and AP-1, has been known for over a decade.
• GR influences other transcription factors without direct DNA binding.
• Recent findings highlight the essential role of GR's cross-talk ability in mouse development.

Purpose of the Study:

• To elucidate the mechanisms and functional significance of transcription factor cross-talk.
• To investigate the distinct roles of GR's cross-talk function versus its direct DNA-binding activity (via glucocorticoid response elements, GREs).
• To explore the potential for dissociating beneficial immune-modulating effects from adverse side effects of corticosteroid treatment.

Main Methods:

• Review of existing experimental data on GR function and cross-talk mechanisms.
• Analysis of mouse models to assess the necessity of GR cross-talk and GRE-mediated activation for survival and development.
• Examination of GR's regulatory actions in the immune system.

Main Results:

• GR cross-talk is essential for mouse development, while GRE-mediated gene activation is dispensable for survival under standard conditions.
• The cross-talk function accounts for nearly all of cortisol's regulatory actions in the immune system.
• GR possesses at least two distinct functions that can potentially be modulated by specific ligands.

Conclusions:

• GR's cross-talk function is critical for development and immune regulation, independent of its direct transcriptional activation via GREs.
• Understanding the differential activation of GR functions may allow for the development of safer corticosteroid therapies.
• Future research should focus on attributing specific adverse effects of corticosteroids to GRE-mediated gene activation to separate them from therapeutic actions.