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Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
Published on: September 21, 2011
Coactivation and corepression in transcriptional regulation by steroid/nuclear hormone receptors
1Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical School, Worcester 01655-0126, USA.
Abstract:
Transcriptional regulation by steroid/nuclear receptors is the central theme of hormone action that controls key aspects of cell differentiation, development, and homeostasis. The molecular mechanisms of gene activation and repression by the receptors have been investigated extensively in recent years. Particularly, several new proteins involved in this signaling pathway have been identified, cloned, and demonstrated to modulate transcription in concert with nuclear receptors. In the absence of hormone, unliganded receptors interact with a family of transcriptional corepressors, including SMRT and N-CoR, which target histone deacetylases to establish a condensed and repressed chromatin structure. Upon hormone binding, the corepressor complex is replaced by a coactivator complex, containing SRC1/TIF2/RAC3 and CBP/p300, which target histone acetyltransferases to generate a transcriptionally accessible chromatin structure. These studies initiate a new era in the history of hormone research and provide novel entry points for understanding the mechanisms of transcriptional regulation by steroid/nuclear receptors.
Insights
Hormone action involves steroid/nuclear receptors regulating gene expression. These receptors interact with corepressors or coactivators to control chromatin structure and gene activity, impacting cell differentiation and homeostasis.
Area of Science:
- Molecular Biology
- Endocrinology
- Epigenetics
Background:
- Steroid/nuclear receptors are crucial for hormone action, controlling cell differentiation, development, and homeostasis.
- Understanding the molecular mechanisms of transcriptional regulation by these receptors is essential.
Purpose of the Study:
- To investigate the mechanisms of gene activation and repression by steroid/nuclear receptors.
- To identify and characterize new proteins involved in this signaling pathway.
Main Methods:
- Identification and cloning of novel proteins modulating transcription with nuclear receptors.
- Analysis of corepressor and coactivator complex interactions with nuclear receptors.
Main Results:
- Unliganded receptors interact with corepressors (SMRT, N-CoR) targeting histone deacetylases, leading to repressed chromatin.
- Hormone binding triggers replacement of corepressors with coactivators (SRC1, TIF2, RAC3, CBP, p300) targeting histone acetyltransferases, creating accessible chromatin.
Conclusions:
- These findings reveal novel entry points for understanding transcriptional regulation by steroid/nuclear receptors.
- The dynamic interplay between receptors, corepressors, and coactivators is central to hormone-mediated gene control.
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