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Functional interactions between Stat5 and the glucocorticoid receptor
E Stöcklin1, M Wissler, F Gouilleux
1Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.
Abstract:
Signal transduction pathways enable extracellular signals to activate latent transcription factors in the cytoplasm of cells. Dimerization, nuclear localization and binding to specific DNA sequences result in the induction of gene transcription by these proteins. These events are necessary for the functioning of the JAK/STAT pathway and of the glucocorticoid-receptor pathway. In the former, the protein Stat5, which is a member of a family of signal transducers and activators of transcription, is activated by cytokines, hormones and growth factors. These polypeptide ligands bind at the outside of the cell to specific transmembrane receptors and activate intracellular Janus protein tyrosine kinases (JAKs) to tyrosine-phosphorylate STAT proteins; interaction with the SH2 domain of the dimerization partner then confers the ability to bind to DNA at the STAT-response element and induce transcription. In the glucocorticoid-receptor pathway, the receptor interacts with its steroid hormone ligand in the cytoplasm, undergoes an allosteric change that enables the hormone receptor complex to bind to specific DNA-response elements (glucocorticoid response elements, or GRE) and modulate transcription. Although these pathways appear to be unrelated, we show here that the glucocorticoid receptor can act as a transcriptional co-activator for Stat5 and enhance Stat5-dependent transcription. Stat5 forms a complex with the glucocorticoid receptor which binds to DNA independently of the GRE. This complex formation between Stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a GRE-containing promoter.
Insights
The glucocorticoid receptor enhances Stat5-dependent transcription by forming a novel complex. This interaction impacts gene regulation, revealing a previously unknown link between these two key signaling pathways.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Gene Regulation
Background:
- Signal transduction pathways regulate gene transcription by activating latent transcription factors.
- The Janus kinase/Signal transducer and activator of transcription (JAK/STAT) and glucocorticoid receptor (GR) pathways are critical for cellular responses.
- Stat5 and GR are key transcription factors activated by distinct extracellular signals.
Purpose of the Study:
- To investigate the potential interaction between the Stat5 and glucocorticoid receptor signaling pathways.
- To determine if the glucocorticoid receptor can influence Stat5-mediated gene transcription.
Main Methods:
- Co-immunoprecipitation assays to detect protein complex formation.
- Reporter gene assays to measure transcriptional activity.
- DNA-binding assays to assess protein-DNA interactions.
Main Results:
- The glucocorticoid receptor physically interacts with Stat5, forming a functional complex.
- This complex enhances Stat5-dependent transcription of target genes.
- The Stat5-GR complex binds to DNA independently of canonical glucocorticoid response elements (GREs).
- The formation of this complex leads to a diminished transcriptional response at GRE-containing promoters.
Conclusions:
- The glucocorticoid receptor acts as a co-activator for Stat5, integrating distinct signaling pathways.
- This novel interaction reveals a cross-talk mechanism influencing gene expression.
- The findings expand our understanding of transcriptional regulation by Stat5 and glucocorticoid receptor.