Corepressor Recruitment by Agonist-Bound Nuclear Receptors

doi:10.1016/S0083-6729(04)68004-6

Vitamins & Hormones

Volume 68, 2004, Pages 123-143

https://doi.org/10.1016/S0083-6729(04)68004-6 Get rights and content

Abstract

Members of the nuclear receptor superfamily are ligand-regulated transcription factors that are composed of a series of conserved domains. These receptors are targets of a wide range of lipophilic signaling molecules that modulate many aspects of physiology and metabolism. Binding of cognate ligands to receptors induces a conformational change in the ligand binding domain (LBD) that creates a pocket for recruitment of coregulatory proteins, which are essential for ligand-dependent regulation of transcription. Several coregulatory proteins that interact with hormone-bound receptors contain characteristic helical LXXLL motifs, known as nuclear receptor (NR) boxes. Generally, ligand binding to receptors is associated with activation of transcription, and most of the NR box-containing proteins characterized to date are coactivators. However, a full understanding of the function of hormone-bound receptors must also incorporate their recruitment of corepressors. The recent identification of ligand-dependent corepressor (LCoR) is a case in point. LCoR contains a single NR box that mediates its hormone-dependent interaction with several nuclear receptors. It functions as a molecular scaffold that recruits several proteins that function in transcriptional repression. Remarkably, although the two proteins share only very limited homology, LCoR and another NR box-containing corepressor RIP140 recruit similar cofactors implicated in transcriptional repression, suggesting many parallels in their mechanisms of action. Corepressors such as LCoR and RIP140 may function in negative feedback loops to attenuate hormone-induced transactivation, act more transiently as part of a cycle of cofactors recruited to target promoters by ligand-bound receptors, or function in hormone-induced target gene repression.

Section snippets

Identification and Cloning of Receptor cdNAs

Nuclear receptors (NRs) are ligand-regulated transcription factors whose activities are controlled by a range of lipophilic extracellular signals. These receptors have been characterized by a variety of experimental approaches over the last few decades. The first nuclear receptors were identified by classical endocrinology techniques as primary intracellular targets of steroid and thyroid hormones (Green and Chambon, 1988; Hollenberg 1985, McKenna 2002). However, the techniques used to identify

Coregulatory Proteins in Hormone-Dependent Regulation of Transcription

By the mid-1990s, it became clear that regulation of transcription by nuclear receptors required specific factors, so-called coregulatory proteins, that functioned between DNA-bound receptors and recruitment of RNA polymerase II and its ancillary transcription factors. The search for coregulators was driven largely by two sets of findings. First, gene transfer experiments showed that different hormone-bound receptors competed for limiting quantities of specific factors that were not required

Histone Deacetylases in Regulation of Gene Expression

Histone deacetylases (HDACs) are widely associated with transcriptional repression. HDACs and their roles in transcriptional regulation have been subjects of intensive study over the last few years. To date, dozens of proteins with HDAC activity have been identified in a wide range of organisms (Grozinger 2002, Khochbin 2001, Yang 2003). Their roles in transcriptional repression arise from the fact that histone deacetylation frees the epsilon amino groups of modified lysines, thereby

LCoR and RIP140 Recruit the Corepressor C-Terminal Binding Protein (CtBP)

The corepressor CtBP interacts with a number of transcription factors. It was originally identified as a factor that interacted with the C-terminal of the adenoviral oncoprotein E1A, and it was shown that mutations in the CtBP binding motif of E1A increase its oncogenicity (Chinnadurai, 2002). Subsequently, highly homologous CtBP2 was identified from EST databases (Katsanis and Fisher, 1998). Recently, biochemical studies have shown that CtBPs are components of a large complex of proteins

Potential Roles of LCoR and RIP140 in Hormone-Dependent Receptor Function

The existence of corepressors such as LCoR and RIP140 that recognize agonist-bound receptors through LXXLL motifs is perhaps counterintuitive. What then are their potential biochemical and physiologic roles? Several experiments have shown that nuclear receptor function is modulated by signals other than ligand binding (McKenna and O'Malley, 2002). There are numerous examples of the effects of phosphorylation on nuclear receptor function (Shao and Lazar, 1999). MAP kinase signaling stimulates

Concluding Remarks

The field has learned much about coregulatory proteins recruited by nuclear receptors since the identification of the first factors in 1995. Much work remains to be done, however, particularly regarding the roles of NR box-containing corepressors in controlling nuclear receptor-regulated transcription. Development of the molecular tools necessary for chromatin immunoprecipitation (ChIP) assays will be very valuable in determining when NR box-containing corepressors, such as RIP140 and LCoR,

Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and the National Cancer Institute of Canada to John H. White, Sylvie Mader, and Xiang-Jiao Yang. Isabelle Fernandes held a postdoctoral fellowship from the CIHR.

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Citation Excerpt :
LCoR is a nuclear protein that interacts with ERα and the repressive activity of which is driven through HDAC and CtBPs recruitment, as described for RIP140 [20–22]. LCoR shows repressive activity in BC cells [19,23], and also inhibits prostate cancer growth in murine models [24]. Moreover, high RIP140 and LCoR mRNA expression were associated with longer survival in a cohort of 183 patients with BC [19].
New markers are needed to improve diagnosis and to personalize treatments for patients with breast cancer (BC). Receptor-interacting protein of 140 kDa (RIP140) and ligand-dependent corepressor (LCoR), two transcriptional co-regulators of estrogen receptors, strongly interact in BC cells. Although their role in cancer progression has been outlined in the last few years, their function in BC has not been elucidated yet. In this study, we investigated RIP140 and LCoR localization (cytoplasm vs nucleus) in BC samples from a well-characterized cohort of patients (n = 320). RIP140 and LCoR were expressed in more than 80% of tumors, (predominantly in the cytoplasm), and the two markers were highly correlated. Expression of RIP140 and LCoR in the nucleus was negatively correlated with tumor size. Conversely, RIP140 and LCoR cytoplasmic expression strongly correlated with expression of two tumor aggressiveness markers: N-cadherin and CD133 (epithelial mesenchymal transition and cancer stem cell markers, respectively). Finally, high RIP140 nuclear expression was significantly correlated with longer overall survival, whereas high total or cytoplasmic expression of RIP140 was associated with shorter disease-free survival. Our study strongly suggests that the role of RIP140 and LCoR in BC progression could vary according to their prevalent sub-cellular localization, with opposite prognostic values for nuclear and cytoplasmic expression. The involvement in BC progression/invasiveness of cytoplasmic RIP140 could be balanced by the anti-tumor action of nuclear RIP140, thus explaining the previous contradictory findings about its role in BC.

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