ArticleMolecular and cellular biology2000
The orphan nuclear receptor SHP utilizes conserved LXXLL-related motifs for interactions with ligand-activated estrogen receptors.
Article in Molecular and cellular biology, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 157 citations in OpenAlex.
- Article
- Article
- Loss of Hepatic Small Heterodimer Partner Elevates Ileal Bile Acids and Alters Cell Cycle-related Genes in Male Mice.Endocrinology · 2022Article
- Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease.Molecular metabolism · 2021Review
- LPS Stimulation Induces Small Heterodimer Partner Expression Through the AMPK-NRF2 Pathway in Large Yellow Croaker (Frontiers in immunology · 2021Article
- Nuclear receptor crosstalk - defining the mechanisms for therapeutic innovation.Nature reviews. Endocrinology · 2020Review
- The regulation of acetylation and stability of HMGA2 via the HBXIP-activated Akt-PCAF pathway in promotion of esophageal squamous cell carcinoma growth.Nucleic acids research · 2020Article
- The nuclear receptor superfamily: A structural perspective.Protein science : a publication of the Protein Society · 2018Review
- Structural Analysis of the Glucocorticoid Receptor Ligand-Binding Domain in Complex with Triamcinolone Acetonide and a Fragment of the Atypical Coregulator, Small Heterodimer Partner.Molecular pharmacology · 2017Article
- HNF-4 participates in the hibernation-associated transcriptional regulation of the chipmunk hibernation-related protein gene.Scientific reports · 2017Article
- Circadian clock control of hepatic lipid metabolism: role of small heterodimer partner (Shp).Journal of investigative medicine : the official publication of the American Federation for Clinical Research · 2016Review
- Modulation of expression of the nuclear receptor NR0B2 (small heterodimer partner 1) and its impact on proliferation of renal carcinoma cells.OncoTargets and therapy · 2016Article
- Liver receptor homolog-1 (LRH-1): a potential therapeutic target for cancer.Cancer biology & therapy · 2015Review
- Negative regulators of brown adipose tissue (BAT)-mediated thermogenesis.Journal of cellular physiology · 2014Review
- Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.Archives of toxicology · 2013Review
- Epigenomic regulation of bile acid metabolism: emerging role of transcriptional cofactors.Molecular and cellular endocrinology · 2013Review
- Xenobiotic-sensing nuclear receptors involved in drug metabolism: a structural perspective.Drug metabolism reviews · 2013Review
- Nuclear hormone receptors in podocytes.Cell & bioscience · 2012Article
- A pleiotropic role for the orphan nuclear receptor small heterodimer partner in lipid homeostasis and metabolic pathways.Journal of lipids · 2012Article
- Ligand-dependent differences in estrogen receptor beta-interacting proteins identified in lung adenocarcinoma cells corresponds to estrogenic responses.Proteome science · 2011Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SHP (short heterodimer partner) is an unusual orphan nuclear receptor consisting only of a ligand-binding domain, and it exhibits unique features of interaction with conventional nuclear receptors. While the mechanistic basis of these interactions has remained enigmatic, SHP has been suggested to inhibit nuclear receptor activation by at least three alternatives; inhibition of DNA binding via dimerization, direct antagonism of coactivator function via competition, and possibly transrepression via recruitment of putative corepressors. We now show that SHP binds directly to estrogen receptors via LXXLL-related motifs. Similar motifs, referred to as NR (nuclear receptor) boxes, are usually critical for the binding of coactivators to the ligand-regulated activation domain AF-2 within nuclear receptors. In concordance with the NR box dependency, SHP requires the intact AF-2 domain of agonist-bound estrogen receptors for interaction. Mutations within the ligand-binding domain helix 12, or binding of antagonistic ligands, which are known to result in an incomplete AF-2 surface, abolish interactions with SHP. Supporting the idea that SHP directly antagonizes receptor activation via AF-2 binding, we demonstrate that SHP variants, carrying either interaction-defective NR box mutations or a deletion of the repressor domain, have lost the capacity to inhibit agonist-dependent transcriptional estrogen receptor activation. Furthermore, our studies indicate that SHP may function as a cofactor via the formation of ternary complexes with dimeric receptors on DNA. These novel insights provide a mechanistic explanation for the inhibitory role of SHP in nuclear receptor signaling, and they may explain how SHP functions as a negative coregulator or corepressor for ligand-activated receptors, a novel and unique function for an orphan nuclear receptor.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.