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The SRC family of nuclear receptor coactivators
1Department of Pharmacology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA, USA.
Abstract:
Nuclear hormone receptors are ligand-dependent transcription factors that regulate genes critical to such biological processes as development, reproduction, and homeostasis. Interestingly, these receptors can function as molecular switches, alternating between states of transcriptional repression and activation, depending on the absence or presence of cognate hormone, respectively. In the absence of hormone, several nuclear receptors actively repress transcription of target genes via interactions with the nuclear receptor corepressors SMRT and NCoR. Upon binding of hormone, these corepressors dissociate away from the DNA-bound receptor, which subsequently recruits a nuclear receptor coactivator (NCoA) complex. Prominent among these coactivators is the SRC (steroid receptor coactivator) family, which consists of SRC-1, TIF2/GRIP1, and RAC3/ACTR/pCIP/AIB-1. These cofactors interact with nuclear receptors in a ligand-dependent manner and enhance transcriptional activation by the receptor via histone acetylation/methylation and recruitment of additional cofactors such as CBP/p300. This review focuses on the mechanism of action of SRC coactivators in terms of interactions with receptors and activation of transcription. Specifically, the roles of the highly conserved LXXLL motifs in mediating SRC function will be detailed. Additionally, potential diversity among SRC family members, as well as several recently cloned SRC-associated cofactors, will be discussed.
Insights
Nuclear hormone receptors act as molecular switches, regulated by ligand binding. Steroid receptor coactivators (SRCs) interact with these receptors to activate gene transcription, playing key roles in biological processes.
Area of Science:
- Molecular Biology
- Genetics
- Endocrinology
Background:
- Nuclear hormone receptors are crucial ligand-dependent transcription factors regulating development, reproduction, and homeostasis.
- These receptors function as molecular switches, transitioning between transcriptional repression (hormone-absent) and activation (hormone-present).
- Corepressors (SMRT, NCoR) mediate repression in the absence of hormone, while coactivators are recruited upon hormone binding.
Purpose of the Study:
- To review the mechanism of action of SRC (steroid receptor coactivator) family coactivators.
- To detail the role of conserved LXXLL motifs in SRC-mediated transcriptional activation.
- To discuss the diversity within the SRC family and newly identified SRC-associated cofactors.
Main Methods:
- Literature review focusing on nuclear receptor coactivators.
- Analysis of molecular interactions between receptors, coactivators, and corepressors.
- Discussion of signaling pathways involving histone modification and cofactor recruitment.
Main Results:
- SRC coactivators (SRC-1, TIF2/GRIP1, RAC3) enhance transcription by interacting with ligand-bound nuclear receptors.
- These coactivators facilitate transcriptional activation through histone acetylation/methylation and recruitment of complexes like CBP/p300.
- The conserved LXXLL motif is critical for SRC family member function.
Conclusions:
- SRC coactivators are essential for ligand-dependent transcriptional activation by nuclear hormone receptors.
- Understanding SRC coactivator mechanisms provides insight into gene regulation in development and homeostasis.
- Further research into SRC family diversity and associated cofactors may reveal new regulatory pathways.