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Nuclear receptors, their coactivators and modulation of transcription
1M. Nencki Institute of Experimental Biology, Warszawa, Poland. mmc@nencki.gov.pl
Abstract:
Nuclear receptors are ligand-dependent transcription factors which can also be activated in the absence of their lipophilic ligands by signaling substances acting on cell membrane receptors. This ligand-independent activation indicates the importance of nuclear receptor phosphorylation for their function. Nuclear receptor-mediated transcription of target genes is further increased by interactions with recruited coactivators forming a novel family of nuclear proteins. CBP/p300, a coactivator of different classes of transcription factors, including the tumor suppressor protein p53, plays a special role acting as a bridging protein between inducible transcription factors and the basal transcription apparatus, and as an integrator of diverse signaling pathways. Coactivators of nuclear receptors and associated proteins forming a multicomponent complex have an intrinsic histone acetylase activity in contrast to nuclear receptor and heterodimer Mad-Max corepressors, which recruit histone deacetylase. Similarly the Rb protein interacts with histone deacetylase to repress transcription of cell cycle regulatory genes. Targeted histone acetylation/deacetylation results in remodeling of chromatin structure and correlates with activation/repression of transcription. Recent data point to the important role of coactivator proteins associated with inducible transcription factors in transcription regulation, and in the integration of multiple signal transduction pathways within the nucleus.
Insights
Nuclear receptors regulate gene transcription and can be activated without ligands through cell signaling. Coactivator proteins, like CBP/p300, are crucial for this process, integrating signals and modifying chromatin structure.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Nuclear receptors are ligand-dependent transcription factors.
- Ligand-independent activation highlights the role of nuclear receptor phosphorylation.
- Coactivators and corepressors modulate nuclear receptor function.
Purpose of the Study:
- To elucidate the mechanisms of nuclear receptor activation and transcriptional regulation.
- To highlight the role of coactivators in integrating signaling pathways.
- To explain the function of histone acetylation and deacetylation in transcription.
Main Methods:
- Review of existing literature on nuclear receptors, coactivators, and chromatin remodeling.
- Analysis of signaling pathways affecting nuclear receptor activity.
- Examination of the interplay between transcription factors, coactivators, and chromatin modifiers.
Main Results:
- Nuclear receptors can be activated independently of ligands via cell surface receptor signaling, involving phosphorylation.
- Coactivators, such as CBP/p300, bridge transcription factors to the basal transcription machinery and integrate signals.
- Coactivator complexes possess histone acetylase activity, while corepressors recruit histone deacetylases, leading to chromatin remodeling and transcriptional changes.
Conclusions:
- Nuclear receptor function is intricately linked to phosphorylation and coactivator recruitment.
- Coactivators play a pivotal role in integrating diverse cellular signals within the nucleus.
- Targeted histone acetylation/deacetylation by coactivator/corepressor complexes is essential for transcriptional regulation and chromatin structure modulation.