Ku proteins function as corepressors to regulate farnesoid X receptor-mediated gene expression

Ohno, Masatomi; Kunimoto, Masaaki; Nishizuka, Makoto; Osada, Shigehiro; Imagawa, Masayoshi

doi:10.1016/j.bbrc.2009.10.040

Cited by 15 publications

(23 citation statements)

References 17 publications

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“…37) Herein we also found that Ku proteins interacted with FTF. Therefore, we next investigated the association of Ku proteins with other nuclear receptors by using the GST pull-down assay.…”

Section: Identification Of Ku Proteins As Proteins Binding With the Amentioning

confidence: 55%

“…The expression plasmids for GST-tagged FXR A-C, FLAG-tagged Ku80, and FLAG-tagged Ku70 were described previously. 37) The expression plasmid of FLAG-tagged mPGC-1a was a gift from Dr. Kamei.…”

Section: Methodsmentioning

confidence: 99%

“…The nuclear receptors tested included FXR (previously shown in ref. 37), TRa, PPARg 1 , ERa and ERb, Rev-erba, and RORa. Among these receptors, FXR, TRa, and PPARg 1 bind to a specific DNA response element as a heterodimeric complex with retinoid X receptor (RXR).…”

Section: Identification Of Ku Proteins As Proteins Binding With the Amentioning

confidence: 99%

“…37) Briefly, 100 mg of GST or GST-FTF A-C was incubated with 1 mg of nuclear extracts from HeLa cells. The bound proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and subjected to negative staining using Negative Gel Stain MS Kit (Wako, Osaka, 293-57701) according to the manufacturer's instructions.…”

Section: Gst Pull-down Assays and Identification Of Ku80 And Ku70mentioning

confidence: 99%

“…We also demonstrated that DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Ku80, and Ku70 associated with FXR, and the Ku proteins (Ku80 and Ku70) functioned as corepressors for FXR. 37) We have attempted independently to search for cofactors that regulate the transactivation activity of LRH-1. Interestingly, we isolated Ku proteins as LRH-1-associating proteins and demonstrated that they decreased the SHP promoter activity mediated by LRH-1.…”

mentioning

confidence: 99%

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Repression of the Promoter Activity Mediated by Liver Receptor Homolog-1 through Interaction with Ku Proteins

Ohno

Komakine

Suzuki

et al. 2010

Biological & Pharmaceutical Bulletin

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The mammalian nuclear receptor superfamily of evolutionarily related DNA-binding transcription factors consists of approximately 50 members, many of which mediate gene expression in a ligand-dependent manner. From their functional similarities, nuclear receptors are divided into A-F regions that include the N-terminal A/B region, the highly conserved DNA-binding domain (DBD; C region), the C-terminal ligand-binding domain (LBD; E/F region), and the D region, which serves as a hinge between the C and the E/F regions. The A/B and the E/F regions contain ligand-independent activation function (AF-1) and ligand-dependent activation function (AF-2), respectively. 1-3) Nuclear receptors regulate gene expression through interactions with coregulator complexes along with the general transcriptional machinery. 4,5) The coregulators associating with the C-terminal region that mediate AF-2 are well documented, whereas the proteins interacting with the N-terminal region that mediate AF-1 and the mechanism involved are not well defined. 6)Liver receptor homolog-1 (LRH-1; NR5A2), part of the nuclear receptor family, is a monomeric orphan receptor initially identified as mammalian homolog of Drosophila Fushi tarazu factor 1 (NR5A3).7-10) The closest mammalian homolog of LRH-1 is steroidogenic factor-1 (SF-1; NR5A1), which is essential for the development and differentiation of steroidgenic tissues and sexual differentiation.11,12) LRH-1 is highly expressed in the liver and intestine involved in enterohepatic circulation, and the ovary. 7,9,13,14) LRH-1 is also expressed in the pancreas, placenta, and pre-adipocyte. 7,15,16) To date, four isoforms of LRH-1, referred to as LRH-1 v1 (NM_205860), 10) LRH-1 (NM_003822), 9,10) fetoprotein transcription factor (FTF; U93553), 17) and LRH-1 v2 (35-323 aa, AF049102), 17) have been reported. The most abundant isoform in liver is LRH-1 (NM_003822) which lacks 46 amino acid residues corresponding to exon 2. 9) LRH-1 v2 is a truncated version of LRH-1 with a deletion in the D region that corresponds to exon5, and does not possess transactivation activity.7) FTF, the N-terminally truncated isoform, is identical to LRH-1 except for a deletion in the A/B region of LRH-1 v1.LRH-1 plays an important role in the homeostasis of bile acids and cholesterol, controlling the expression of a number of genes, including small heterodimer partner (SHP; NR0B2) 18,19) and enzymes for the conversion of cholesterol to bile acids (CYP7A1 and CYP8B1) 10,20) and for high density lipoprotein-remodeling.21) In addition, LRH-1 contributes to development and ovulation.14,22,23) Unlike most nuclear receptors, LRH-1 binds to the LRH-1 response element (LRHRE) (5Ј-YCAAGGYCR-3Ј, Y; pyrimidine, R; purine), three base-pairs longer than the consensus nuclear receptor half-site, as a monomer. 7)Nuclear receptors typically regulate transcription in a ligand-dependent fashion. The binding of a ligand causes the repositioning of helix 12 within the LBD resulting in interaction with the coactivators.1-3) However, the mechanisms...

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Section: Identification Of Ku Proteins As Proteins Binding With the Amentioning

confidence: 55%

Section: Methodsmentioning

confidence: 99%

Section: Identification Of Ku Proteins As Proteins Binding With the Amentioning

confidence: 99%

Section: Gst Pull-down Assays and Identification Of Ku80 And Ku70mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Repression of the Promoter Activity Mediated by Liver Receptor Homolog-1 through Interaction with Ku Proteins

Ohno

Komakine

Suzuki

et al. 2010

Biological & Pharmaceutical Bulletin

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DNA-PK, a Pharmacological Target in Cancer Chemotherapy and Radiotherapy?

Salles

Calsou

Mirey

2012

Advances in DNA Repair in Cancer Therapy

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Role of farnesoid X receptor in inflammation and resolution

2014

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FXR is highly expressed in liver, intestine, kidney and adrenals, but with lower expression in fat tissue, heart and recently it has been found to express in lungs too. Primary bile acids, cholic acid and chenodeoxycholic acid are the natural endogenous ligands for FXR. GW4064 and 6α-ethyl-chenodeoxycholic acid are the synthetic high-affinity agonists. An exhaustive literature survey revealed that FXR acts as a key metabolic regulator and potential drug target for many metabolic syndromes that include chronic inflammatory diseases.

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Ku proteins function as corepressors to regulate farnesoid X receptor-mediated gene expression

Cited by 15 publications

References 17 publications

Repression of the Promoter Activity Mediated by Liver Receptor Homolog-1 through Interaction with Ku Proteins

Repression of the Promoter Activity Mediated by Liver Receptor Homolog-1 through Interaction with Ku Proteins

DNA-PK, a Pharmacological Target in Cancer Chemotherapy and Radiotherapy?

Role of farnesoid X receptor in inflammation and resolution

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