Novel Polymorphisms of Nuclear Receptor SHP Associated with Functional and Structural Changes

Zhou, Taofeng; Zhang, Yuxia; Macchiarulo, Antonio; Yang, Zhihong; Cellanetti, Marco; Coto, Eliécer; Xu, Pingyi; Pellicciari, Roberto; Wang, Li

doi:10.1074/jbc.m110.133280

Cited by 41 publications

(64 citation statements)

References 41 publications

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“…After 24 hours, wild‐type AURKA 3′‐UTR and LIN28B 3′‐UTR or their seed mutant luciferase reporter vectors with miR‐26a‐5p mimic or miR‐29a‐3p mimic were transfected into the cells using RNAiMAX transfection reagent. The dual‐luciferase reporter assay system (Promega, Madison, WI) was applied 48 hours after transfection to determine changes in relative luciferase units as described 24. All assays were performed in triplicate, and all values were normalized for transfection efficiency against Renilla luciferase activities.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

Zhang

Zhao

et al. 2018

Hepatology Communications

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Hepatoblastoma (HB) is the most common liver tumor in children. Despite recent improvements in treatment strategies, the survival of children with hepatoblastoma remains poor. In this study, we identified a novel role of microRNA‐26a‐5p (miR‐26a‐5p), lin‐28 homolog B (LIN28B), Ras‐related nuclear protein (RAN), and aurora kinase A (AURKA) in HB. The expression of LIN28B, RAN, and AURKA was significantly up‐regulated in human HB livers and cell lines. Knockdown of LIN28B and RAN by small interfering RNAs inhibited HB tumor cell proliferation and foci formation. We also elucidated miR‐26a‐5p‐mediated translational inhibition of LIN28B and AURKA in HB. Overexpression of miR‐26a‐5p markedly decreased LIN28B and AURKA 3′‐untranslated region activities and protein expression and repressed HB cell proliferation and colony formation. In contrast, re‐expression of LIN28B and AURKA rescued miR‐26a‐5p‐mediated suppression of HB cell growth and clonality. Importantly, a decreased miR‐26a‐5p expression correlated with the poor outcome of patients with HB. Conclusion: miR‐26a‐5p is a newly identified repressor of HB growth through its inhibition of the oncogenic LIN28B–RAN–AURKA pathway. (Hepatology Communications 2018;2:481‐491)

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Section: Methodsmentioning

confidence: 99%

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

Zhang

Zhao

et al. 2018

Hepatology Communications

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“…Mutations in the SHP-EID1 interface disrupt EID1 binding to SHP. Together, these results provide crucial mechanistic insights into SHP-mediated cofactor recruitment and repression (24,28,30).…”

Section: Arillmastlknipgtllvdlffrpimgdvditelledmlllr-aelnsalfllrfinsdmentioning

confidence: 80%

“…A number of proteins have been isolated as SHP corepressors, including histone deacetylases (SIRT1, HDAC1, and HDAC3) (25,28) and EID1, which inhibits p300/CBP HAT activity (24,26,27). However, the mechanism whereby these corepressors interact with SHP has been poorly understood.…”

Section: Arillmastlknipgtllvdlffrpimgdvditelledmlllr-aelnsalfllrfinsdmentioning

confidence: 99%

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Structural insights into gene repression by the orphan nuclear receptor SHP

Zhi

Zhou

et al. 2013

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

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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

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“…This was accompanied by increased recruitment of HNF4a to the promoter of CYP2D6 (Koh et al, 2014). The enhanced HNF4a activity during pregnancy was attributed in part to the decreased expression of small heterodimer partner (SHP) (Koh et al, 2014), a corepressor that inhibits HNF4a activity via physical interaction (Zhou et al, 2010). Interestingly, our results showed that other target genes of HNF4a (such as Hes6 and ApoC2) did not exhibit similar increases in expression to CYP2D6 during pregnancy in tg-CYP2D6 mice (Koh et al, 2014).…”

Section: Introductionmentioning

confidence: 68%

Krüppel-Like Factor 9 Promotes Hepatic Cytochrome P450 2D6 Expression during Pregnancy in CYP2D6-Humanized Mice

et al. 2014

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Cytochrome P450 2D6 (CYP2D6), a major drug-metabolizing enzyme, is responsible for metabolism of approximately 25% of marketed drugs. Clinical evidence indicates that metabolism of CYP2D6 substrates is increased during pregnancy, but the underlying mechanisms remain unclear. To identify transcription factors potentially responsible for CYP2D6 induction during pregnancy, a panel of genes differentially expressed in the livers of pregnant versus nonpregnant CYP2D6-humanized (tg-CYP2D6) mice was compiled via microarray experiments followed by realtime quantitative reverse-transcription polymerase chain reaction (qRT-PCR) verification. As a result, seven transcription factorsactivating transcription factor 5 (ATF5), early growth response 1 (EGR1), forkhead box protein A3 (FOXA3), JUNB, Krüppel-like factor 9 (KLF9), KLF10, and REV-ERBa-were found to be up-regulated in liver during pregnancy. Results from transient transfection and promoter reporter gene assays indicate that KLF9 itself is a weak transactivator of CYP2D6 promoter but significantly enhances CYP2D6 promoter transactivation by hepatocyte nuclear factor 4 (HNF4a), a known transcriptional activator of CYP2D6 expression. The results from deletion and mutation analysis of CYP2D6 promoter activity identified a KLF9 putative binding motif at -22/-14 region to be critical in the potentiation of HNF4a-induced transactivation of CYP2D6. Electrophoretic mobility shift assays revealed a direct binding of KLF9 to the putative KLF binding motif. Results from chromatin immunoprecipitation assay showed increased recruitment of KLF9 to CYP2D6 promoter in the livers of tg-CYP2D6 mice during pregnancy. Taken together, our data suggest that increased KLF9 expression is in part responsible for CYP2D6 induction during pregnancy via the potentiation of HNF4a transactivation of CYP2D6.

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Novel Polymorphisms of Nuclear Receptor SHP Associated with Functional and Structural Changes

Cited by 41 publications

References 41 publications

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

Structural insights into gene repression by the orphan nuclear receptor SHP

Krüppel-Like Factor 9 Promotes Hepatic Cytochrome P450 2D6 Expression during Pregnancy in CYP2D6-Humanized Mice

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