Nuclear Receptors and Their Selective Pharmacologic Modulators

Burris, Thomas P.; Solt, Laura A.; Wang, Yongjun; Crumbley, Christine; Banerjee, Subhashis; Griffett, Kristine; Lundåsen, Thomas; Hughes, Travis S.; Kojetin, D.J.

doi:10.1124/pr.112.006833

Cited by 229 publications

(249 citation statements)

References 857 publications

(893 reference statements)

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“…Therefore, LdNR are central for nutrigenomics, where protein abundance of the LdNR can govern the sensitivity of the cell to the specific food-derived agonists. However, their activity is primarily determined by the abundance and potency of the agonist(s) (42).…”

Section: Main Factors Controlling Transcription Of Genesmentioning

confidence: 99%

“…The TF are proteins that, when activated by hormones, nutritional molecules, or other factors, are able to recognize specific regions of the DNA referred as the response element (RE) and trigger all events necessary for enhancing or inhibiting the expression of target genes (213). The ligand-dependent nuclear receptors (LdNR) are TF-present in the nucleus (or possess the capability to enter the nucleus upon activation) and can be activated by specific exogenous or endogenous ligands, especially food-derived compounds (42). Therefore, LdNR are central for nutrigenomics, where protein abundance of the LdNR can govern the sensitivity of the cell to the specific food-derived agonists.…”

Section: Main Factors Controlling Transcription Of Genesmentioning

confidence: 99%

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Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

Osorio

Lohakare

Bionaz

2016

Physiological Genomics

189

182

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Section: Main Factors Controlling Transcription Of Genesmentioning

confidence: 99%

Section: Main Factors Controlling Transcription Of Genesmentioning

confidence: 99%

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

Osorio

Lohakare

Bionaz

2016

Physiological Genomics

189

182

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“…The LBD of NRs is generally composed of 12 ␣-helices arranged in a three-layered bundle that forms a hydrophobic ligand pocket. In the absence of ligand, some NRs, such as the thyroid hormone receptor (THR) and retinoic acid receptor, repress gene expression by interacting with transcription corepressors including nuclear receptor corepressor 1 (NCoR1) and silencing mediator of retinoid and thyroid receptors (SMRT) (24); binding of NR antagonists can also lead to corepressor recruitment (25). Both NCoR1 and SMRT are large (Ͼ250 kDa) pro-teins that bind histone deacetylase complexes and contain multiple NR interaction domains at their C termini (26).…”

mentioning

confidence: 99%

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

Carter

Gupta

Ragsdale

2016

Journal of Biological Chemistry

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Rev-erb␣ and Rev-erb␤ are heme-binding nuclear receptors (NR) that repress the transcription of genes involved in regulating metabolism, inflammation, and the circadian clock. Previous gene expression and co-immunoprecipitation studies led to a model in which heme binding to Rev-erb␣ recruits nuclear receptor corepressor 1 (NCoR1) into an active repressor complex. However, in contradiction, biochemical and crystallographic studies have shown that heme decreases the affinity of the ligand-binding domain of Rev-erb NRs for NCoR1 peptides. One explanation for this discrepancy is that the ligand-binding domain and NCoR1 peptides used for in vitro studies cannot replicate the key features of the full-length proteins used in cellular studies. However, the combined in vitro and cellular results described here demonstrate that heme does not directly promote interactions between full-length Rev-erb␤ (FLRev-erb␤) and an NCoR1 construct encompassing all three NR interaction domains. NCoR1 tightly binds both apo-and heme-replete FLRev-erb␤⅐DNA complexes; furthermore, heme, at high concentrations, destabilizes the FLRev-erb␤⅐NCoR1 complex. The interaction between FLRev-erb␤ and NCoR1 as well as Reverb␤ repression at the Bmal1 promoter appear to be modulated by another cellular factor(s), at least one of which is related to the ubiquitin-proteasome pathway. Our studies suggest that heme is involved in regulating the degradation of Rev-erb␤ in a manner consistent with its role in circadian rhythm maintenance. Finally, the very slow rate constant (10 ؊6 s ؊1 ) of heme dissociation from Rev-erb␤ rules out a prior proposal that Reverb␤ acts as an intracellular heme sensor.Nuclear receptors (NRs) 2 are eukaryotic transcription factors that activate or repress gene expression in response to binding small signaling molecules such as steroid hormones, lipophilic vitamins, and fatty acids (1). Genes regulated by NRs are involved in a myriad of cellular processes ranging from metabolic homeostasis to growth and development. The subjects of this article, Rev-erb␣ and Rev-erb␤, are NRs that have overlapping functions and tissue expression patterns (2-9) and are under circadian control (10 -12). Rev-erb NRs repress the transcription of key genes, e.g. Bmal1, CLOCK, and Rev-erb␣ itself, involved in regulating the molecular clock (13)(14)(15). This is accomplished in part through the formation of a heterodimeric Bmal1-CLOCK complex that activates the transcription of clock-controlled genes including Rev-erb␣/␤, completing a critical feedback loop required for circadian rhythm maintenance (6, 7). Rev-erb␣ and Rev-erb␤ also regulate the expression of genes involved in gluconeogenesis, lipid homeostasis, and immune responses, ultimately synchronizing these processes to the diurnal cycle (16 -21).The multiple functions of NRs (DNA, ligand, and coregulator binding) are accomplished through their modular structure (22, 23). The N-terminal A/B domain is hypervariable, is involved in ligand-independent transcriptional regulation, and is subject to ...

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“…It should be kept in mind that different algorithms could give rise to different structural prediction and possibly different binding affinities [21,[24][25][26] . The acquired SERM resistance in breast cancer cells has been studied, especially with respect to long-term treatment [27][28][29][30][31][32] . Interestingly, ER expression is maintained in the acquired resistant tumors [29] .…”

Section: Discussionmentioning

confidence: 99%

Effect of single mutagenesis on the binding pocket of canine estrogen receptor alpha: Structure and binding affinity

et al. 2016

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Hormone-related mammary gland tumors are among the most commonly diagnosed neoplasms in female dogs. Estrogen enacts its biological roles through specific receptors known as estrogen receptors (ER). In human medicine, anti-estrogen therapy has become the gold standard in ER-positive breast tumors' therapeutic regimen. The binding pocket of the canine estrogen receptor alpha (cERα) ligand binding domain comprises of three key amino acid residues including E354, G522 and L526, which stabilize the cERα-E2 interaction via hydrogen bonding. The side chain of E354 shares hydrogen bond interaction with the A ring of its natural ligand E2, whereas the main chain of G522 and L526 interact with the E2-D ring. The single mutation of the E354 aberrant, along with the hydrogen bond interaction between cERα and both ligands, leads to a variety of binding affinities. According to this in silico model, it may be concluded that E354 plays a role in the cERα activities. The effects of single mutants might need to be studied further in vitro and in vivo.

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Nuclear Receptors and Their Selective Pharmacologic Modulators

Cited by 229 publications

References 857 publications

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

Biosynthesis of milk fat, protein, and lactose: roles of transcriptional and posttranscriptional regulation

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

Effect of single mutagenesis on the binding pocket of canine estrogen receptor alpha: Structure and binding affinity

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