Adamantyl-Substituted Retinoid-Related Molecules Bind Small Heterodimer Partner and Modulate the Sin3A Repressor

Farhana, Lulu; Dawson, Marcia I.; Leid, Mark; Wang, Li; Moore, David D.; Liu, Gang; Xia, Zeben; Fontana, Joseph A.

doi:10.1158/0008-5472.can-06-2164

Cited by 70 publications

(107 citation statements)

References 44 publications

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…Indeed, recent reports indicate that SHP associates with N-CoR in vivo despite the absence of a physical interaction (21) and that binding of adamantyl-substituted retinoid-related molecules to SHP results in the recruitment of N-CoR and GPS2-containing corepressor complexes (23).…”

Section: Resultsmentioning

confidence: 99%

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

Sanyal

Båvner

Haroniti

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Coordinated regulation of bile acid biosynthesis, the predominant pathway for hepatic cholesterol catabolism, is mediated by few key nuclear receptors including the orphan receptors liver receptor homolog 1 (LRH-1), hepatocyte nuclear factor 4␣ (HNF4␣), small heterodimer partner (SHP), and the bile acid receptor FXR (farnesoid X receptor). Activation of FXR initiates a feedback regulatory loop via induction of SHP, which suppresses LRH-1-and HNF4␣-dependent expression of cholesterol 7␣ hydroxylase (CYP7A1) and sterol 12␣ hydroxylase (CYP8B1), the two major pathway enzymes. Here we dissect the transcriptional network governing bile acid biosynthesis in human liver by identifying GPS2, a stoichiometric subunit of a conserved corepressor complex, as a differential coregulator of CYP7A1 and CYP8B1 expression. Direct interactions of GPS2 with SHP, LRH-1, HNF4␣, and FXR indicate alternative coregulator recruitment strategies to cause differential transcriptional outcomes. In addition, species-specific differences in the regulation of bile acid biosynthesis were uncovered by identifying human CYP8B1 as a direct FXR target gene, which has implications for therapeutic approaches in bile acid-related human disorders.cholesterol 7␣ hydroxylase ͉ sterol 12␣ hydroxylase ͉ farnesoid X receptor ͉ small heterodimer partner B ile acids (BAs) are cholesterol derivatives essential for absorption of dietary lipids and fat-soluble vitamins and maintenance of cholesterol BA homeostasis (1, 2). In humans the major BA biosynthetic pathway is initiated by cholesterol 7␣ hydroxylase (CYP7A1) to produce two primary BAs, cholic acid and chenodeoxycholic acid (CDCA). Sterol 12␣ hydroxylase (CYP8B1) catalyzes the synthesis of cholic acid and determines the ratio of cholic acid to CDCA in the bile (1). In addition to emulsification of dietary lipids, cholic acid and CDCA are ligands for farnesoid X receptor (FXR/NR1H4) (3-5). Ligandbound FXR regulates a number of target genes involving BA transport and metabolism (6). BAs also feedback-regulate BA biosynthesis, where activated FXR induces small heterodimer partner (SHP/NR0B2) gene expression, and SHP in turn inhibits liver receptor homolog 1 (LRH-1/NR5A2) or hepatocyte nuclear factor 4␣ (HNF4␣/NR2A1) activities on the BA response elements (BAREs) of CYP7A1 and CYP8B1 promoters (7-10). BAs can also act via FXR-independent pathways that use PKC (11) and JNK signaling (12, 13) to suppress HNF4␣-mediated expression of human CYP8B1 (hCYP8B1) (10,11,14). Although the physiological role of SHP in BA biosynthesis is well documented, mechanistic details of repression by SHP remain unclear. Recent studies indicate that SHP may repress its targets (i) via direct binding and blocking the coactivator interaction interface of its target nuclear receptors (NRs), (ii) by antagonizing CREB binding protein (CBP)/p300-dependent coactivator functions on NRs via recruitment of a coinhibitor protein like EID1, and (iii) by recruiting corepressor complexes that include histone deacetylases (HDAC) 1, 3, and 6, Sin3A...

show abstract

Section: Resultsmentioning

confidence: 99%

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

Sanyal

Båvner

Haroniti

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Whereas some of the ARRs such as 6-[3′-(1-adamantyl)-4′-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) may bind to certain nuclear retinoic acid receptors and several may activate this receptor, retinoic acid receptor binding and activation do not seem to play any role in their induction of cell death (24)(25)(26). We have recently discovered that the ARRs specifically bind to the small heterodimer partner SHP (27). In turn, ARR binding of SHP led to Sin3A/SHP complex formation, resulting in modification of the Sin3A complex members as well enhancement of Sin3A-associated HDAC activity (27).…”

Section: Introductionmentioning

confidence: 99%

“…We have recently discovered that the ARRs specifically bind to the small heterodimer partner SHP (27). In turn, ARR binding of SHP led to Sin3A/SHP complex formation, resulting in modification of the Sin3A complex members as well enhancement of Sin3A-associated HDAC activity (27). Although SHP binding to the ARRs and the recruitment of SHP/ARR to Sin3A are clear, the role of SHP, if any, in the modification of a Sin3A complex and enhancement of Sin3A-associated HDAC activity remains to be delineated.…”

Section: Introductionmentioning

confidence: 99%

SHP and Sin3A expression are essential for adamantyl-substituted retinoid-related molecule–mediated nuclear factor-κB activation, c-Fos/c-Jun expression, and cellular apoptosis

Farhana

Dawson²,

Xu³

et al. 2009

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, synthetic retinoidlike compounds such as 3-Cl-AHPC have been shown to bind and regulate SHP activity (34)(35)(36). We speculate that binding of these pharmacophores might rearrange the kinked helix H10, thus allowing formation of the AF-2 cofactor-binding pocket.…”

Section: Arillmastlknipgtllvdlffrpimgdvditelledmlllr-aelnsalfllrfinsdmentioning

confidence: 93%

“…SHP-mediated repression is abolished in mice lacking FGF15, leading to abnormally high levels of CYP7A1 expression and fecal bile acid excretion (33). A number of retinoid-like compounds have been shown to bind to SHP and enhance its repression of CYP7A1 and CYP8B1 in liver cells (34)(35)(36). These findings underscore the importance of understanding the functional and structural basis for SHP's inhibitory function, which could serve as a drug target for treating metabolic diseases arising from bile acid and cholesterol imbalances.…”

Section: Significancementioning

confidence: 99%

Structural insights into gene repression by the orphan nuclear receptor SHP

Zhi

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The undersigned authors wish to note, "The KefFC system of E. coli is maintained in an inactive state by the binding of glutathione (GSH) and is activated by the formation of GSH adducts (GSX), particularly those with bulky substituents. We described two crystal structures with density present in the ligand-binding domain that we interpreted as GSH and GSX. Recently, an independent, experienced crystallographer, who had viewed the structures from our study in a different context, made representations to us that cast doubt on position of the succinimido ring of GSX. We have further reviewed the density maps with the aid of an experienced crystallographer. As a consequence, we believe it is important to draw this altered interpretation of the crystal structures to the attention of readers. In both structures, the density for the backbone of GSH is clear and allows unequivocal assignment of the position of the tripeptide. In PDB coordinate set 3L9X, the density for the succinimido ring is very weak, making interpretation very speculative and the assignment rests on the identity of the ligand added to the crystallization mixture, for which there are two diastereomers in the solutiona possibility that provides some basis for weakening the density. However, in 3L9W there are two anomalies that affect the interpretation of the bound ligand. First, there is no density for the carbon atom attached to the sulfur of GSH and second, there is extra density adjacent to the position of sulfur that could be modelled as a constrained succinimido ring. However, this density could also be water or any other molecule that is trapped in the structure. Thus, while there is good evidence for the peptide, the evidence that it is in the GSH form is uncertain."There are no new data on either the structures or on the gating mechanism. However, we believe that we should be cautious in interpreting the structural data and that the field in general should be made aware of the alternative views of the electron density data. Note that the mutagenesis and spectroscopic data that were presented in the original manuscript are not affected by this alternative interpretation." Tarmo P. The authors note that the following grant should be added to the Acknowledgments: "NIH Grant AG002132." The authors note "The method used for exogenous expression of Ca V 1.2 channels in ref. 32 was incorrectly described as 'viral transduction' in the text. In fact, Yang et al. created transgenic mice with inducible, cardiomyocyte-specific expression of exogenous Ca V 1.2 channels regulated by a tetracycline-inducible promoter. When crossed with a transgenic mouse line expressing doxycycline-regulated reverse transcriptional activator under control of the α-myosin heavy chain protomer, the resulting double transgenic offspring expressed exogenous Ca V 1.2 channels in their cardiac myocytes after treatment with doxycycline. The authors regret the error in describing these methods."www.pnas.org/cgi

show abstract

Adamantyl-Substituted Retinoid-Related Molecules Bind Small Heterodimer Partner and Modulate the Sin3A Repressor

Cited by 70 publications

References 44 publications

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis

SHP and Sin3A expression are essential for adamantyl-substituted retinoid-related molecule–mediated nuclear factor-κB activation, c-Fos/c-Jun expression, and cellular apoptosis

Structural insights into gene repression by the orphan nuclear receptor SHP

Contact Info

Product

Resources

About