Casein Kinase 2 (CK2)-mediated Phosphorylation of Hsp90β as a Novel Mechanism of Rifampin-induced MDR1 Expression

Kim, So Won; Hasanuzzaman, Md.; Cho, Munju; Heo, Ye Rang; Ryu, Min-Jung; Ha, N. Long; Park, Hyun June; Park, Hyung-Yeon; Shin, Jae‐Gook

doi:10.1074/jbc.m114.624106

Cited by 27 publications

(24 citation statements)

References 35 publications

(31 reference statements)

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“…This in turn prolongs the stability and occupancy of the active transcription complex as a whole at the promoter accounting for increased ligand-dependent transcription [98]. This study is corroborated by another report showing that mdr1 (PXR target) gene induction is likely due to increased PXR stability via phosphorylation of its chaperone, heat shock protein (Hsp) 90β [99]. Ligand-induced conformational change of PXR promotes rearrangement of the transcriptional complex into a maximally activated state involving additional p300 recruitment and histone acetylation, thereby accelerating transcription (Fig 7.2).…”

Section: Discussionsupporting

confidence: 53%

Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity

Pasquel¹,

Doricakova²,

Li³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Pregnane X receptor (PXR) is a major transcriptional regulator of xenobiotic metabolism and transport pathways in the liver and intestines, which are critical for protecting organisms against potentially harmful xenobiotic and endobiotic compounds. Inadvertent activation of drug metabolism pathways through PXR is known to contribute to drug resistance, adverse drug–drug interactions, and drug toxicity in humans. In both humans and rodents, PXR has been implicated in non-alcoholic fatty liver disease, diabetes, obesity, inflammatory bowel disease, and cancer. Because of PXR's important functions, it has been a therapeutic target of interest for a long time. More recent mechanistic studies have shown that PXR is modulated by multiple PTMs. Herein we provide the first investigation of the role of acetylation in modulating PXR activity. Through LC–MS/MS analysis, we identified lysine 109 (K109) in the hinge as PXR's major acetylation site. Using various biochemical and cell-based assays, we show that PXR's acetylation status and transcriptional activity are modulated by E1A binding protein (p300) and sirtuin 1 (SIRT1). Based on analysis of acetylation site mutants, we found that acetylation at K109 represses PXR transcriptional activity. The mechanism involves loss of RXRα dimerization and reduced binding to cognate DNA response elements. This mechanism may represent a promising therapeutic target using modulators of PXR acetylation levels.

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Section: Discussionsupporting

confidence: 53%

Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity

Pasquel¹,

Doricakova²,

Li³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…In vitro studies using cells derived from intestinal tissues have indicated the pregnane-X receptor as a key player in drug-induced P-gp expression (Maier et al, 2007;Kim et al, 2015). For example, rifampin induces P-gp via casein kinase 2-mediated phosphorylation of heat shock protein 90b, and subsequent stabilization of the pregnane-X receptor (Kim et al, 2015). Thus, increased activation of the pregnane-X receptor might be a good candidate to investigate as a possible mechanism of calorie restriction-induced P-gp expression.…”

Section: Discussionmentioning

confidence: 99%

Calorie Restriction Increases P-Glycoprotein and Decreases Intestinal Absorption of Digoxin in Mice

Renaud

Klaassen

Csanaky

2016

Drug Metabolism and Disposition

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There is wide variation in how patients respond to therapeutics. Factors that contribute to pharmacokinetic variations include disease, genetics, drugs, age, and diet. The purpose of this study was to determine the effect of calorie restriction on the expression of Abcb1a in the intestine and whether calorie restriction can alter the absorption of an Abcb1a substrate (i.e., digoxin) in mice. Ten-week-old C57BL/6 mice were given either an ad libitum diet or a 25% calorie-restricted diet for 3 weeks. To determine digoxin absorption, mice were administered [ 3 H]-labeled digoxin by oral gavage. Blood and intestine with contents were collected at 1, 2, 4, and 12 hours after digoxin administration. Concentrations of [ 3 H]-digoxin in plasma and tissues were determined by liquid scintillation. Calorie restriction decreased plasma digoxin concentrations (about 60%) at 1, 2, and 4 hours after administration. Additionally, digoxin concentrations in the small intestine of calorie-restricted mice were elevated at 4 and 12 hours after administration. Furthermore, calorie restriction increased Abcb1a transcripts in the duodenum (4.5-fold) and jejunum (12.5-fold). To confirm a role of Abcb1a in the altered digoxin pharmacokinetics induced by calorie restriction, the experiment was repeated in Abcb1a/ b-null mice 4 hours after drug administration. No difference in intestine or plasma digoxin concentrations were observed between ad libitumfed and calorie-restricted Abcb1a/b-null mice. Thus, these findings support the hypothesis that calorie restriction increases intestinal Abcb1a expression, leading to decreased absorption of digoxin in mice. Because Abcb1a transports a wide variety of therapeutics, these results may be of important clinical significance.

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“…DYRK2 phosphorylates hPXR and facilitates hPXR ubiquitination by UBR5 [104]. In addition to ubiquitination, PXR stabilization was also regulated by the chaperone protein heat-shock protein 90β (Hsp90β) [105]. RIF-activated casein kinase 2 (CK2) was shown to phosphorylate Hsp90β at serine 225 and serine 254.…”

Section: Regulation Of Pxr Through Protein-protein Interaction Andmentioning

confidence: 99%

“…RIF-activated casein kinase 2 (CK2) was shown to phosphorylate Hsp90β at serine 225 and serine 254. The phosphorylation of Hsp90β increased its interaction with PXR and promoted PXR stabilization, consequently increasing the expression of MDR1—an essential mediator of multidrug resistance [105]. …”

Section: Regulation Of Pxr Through Protein-protein Interaction Andmentioning

confidence: 99%

Regulation of PXR and CAR by protein-protein interaction and signaling crosstalk

Oladimeji

Cui

Zhang

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction Protein-protein interaction and signaling crosstalk contribute to the regulation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) and broaden their cellular function. Area covered This review covers key historic discoveries and recent advances in our understanding of the broad function of PXR and CAR and their regulation by protein-protein interaction and signaling crosstalk. Expert opinion PXR and CAR were first discovered as xenobiotic receptors. However, it is clear that PXR and CAR perform a much broader range of cellular functions through protein-protein interaction and signaling crosstalk, which typically mutually affect the function of all the partners involved. Future research on PXR and CAR should, therefore, look beyond their xenobiotic function.

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Casein Kinase 2 (CK2)-mediated Phosphorylation of Hsp90β as a Novel Mechanism of Rifampin-induced MDR1 Expression

Cited by 27 publications

References 35 publications

Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity

Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity

Calorie Restriction Increases P-Glycoprotein and Decreases Intestinal Absorption of Digoxin in Mice

Regulation of PXR and CAR by protein-protein interaction and signaling crosstalk

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