PDZK1 Regulates Breast Cancer Resistance Protein in Small Intestine

Shimizu, Takuya; Sugiura, Tomoko; Wakayama, Tomohiko; Kijima, Ai; Nakamichi, Noritaka; Iseki, Shoichi; Silver, David L.; Kato, Yukio

doi:10.1124/dmd.111.040295

Cited by 43 publications

(39 citation statements)

References 36 publications

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“…This may be partly because of the difference of the investigated population and/or because of the limited sample (2043 individuals). Our result with patients with gout does not deny the presence of urate transportsome involving PDZK1 because the association between rs12129861 and SUA 1,10 , as well as the molecular interaction among PDZK1 and urate transporters 6,7,8,9 , has already been reported. Nevertheless, the advantage of our study is the quality of the cases: all of the patients with gout who participated in our study were diagnosed by Figure 1.…”

Section: To the Editormentioning

confidence: 75%

“…PDZK1 (also known as NHERF3) is a scaffolding protein that binds to several urate transporters such as URAT1, OAT4, and NPT1. As for ABCG2, the interaction with PDZK1 is shown to be weak (dotted line) 9 . Together with NHERF1, which also scaffolds urate transporters (OAT4, NPT1, and MRP4), PDZK1 plays a pivotal role in forming a urate-transporting multimolecular complex (urate transportsome) in humans.…”

Section: To the Editormentioning

confidence: 99%

“…PDZ domain containing 1 (PDZK1, also known as NHERF3) plays a pivotal role as a scaffolding protein that forms urate transportsome 6,7,8,9 with URAT1, ABCG2, and OAT4 (Figure 1). A single-nucleotide polymorphism (SNP), rs12129861, was first reported to have an association between PDZK1 gene and SUA 1 , which was confirmed by a replication study 10 .…”

Section: To the Editormentioning

confidence: 99%

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Common Variant of PDZK1, Adaptor Protein Gene of Urate Transporters, is Not Associated with Gout

et al. 2014

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Section: To the Editormentioning

confidence: 75%

Section: To the Editormentioning

confidence: 99%

Section: To the Editormentioning

confidence: 99%

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Common Variant of PDZK1, Adaptor Protein Gene of Urate Transporters, is Not Associated with Gout

et al. 2014

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“…MDCKII cells stably expressing both BCRP and PDZK1 (MDCKII/BCRP/PDZK1 cells) and those stably expressing PDZK1 alone (MDCKII/mock/PDZK1) were previously obtained (Shimizu et al, 2011), and were grown in Dulbecco's modified Eagle's medium containing 10% fetal calf serum, penicillin, streptomycin, 1 mg/ml geneticin, and 0.2 mg/ml zeocin in a humidified incubator at 37°C under an atmosphere of 5% CO 2 in air. MDCKII/BCRP/PDZK1 and MDCKII/mock/ PDZK1 cells were seeded in Transwell polycarbonate inserts (3 mm pore size, 12 mm diameter; Corning Life Sciences, Edison, NJ) at a density of 3 Â 10 5 cells/well.…”

Section: Methodsmentioning

confidence: 99%

Interaction of Novel Platelet-Increasing Agent Eltrombopag with Rosuvastatin via Breast Cancer Resistance Protein in Humans

et al. 2014

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Eltrombopag (ELT), an orally available thrombopoietin receptor agonist, is a substrate of organic anion transporting polypeptide 1B1 (OATP1B1), and coadministration of ELT increases the plasma concentration of rosuvastatin in humans. Since the pharmacokinetic mechanism(s) of the interaction is unknown, the present study aimed to clarify the drug interaction potential of ELT at transporters. The OATP1B1-mediated uptake of ELT was inhibited by several therapeutic agents used to treat lifestyle diseases. Among them, rosuvastatin was a potent inhibitor with an IC 50 of 0.05 mM, which corresponds to one-seventh of the calculated maximum unbound rosuvastatin concentration at the inlet to the liver. Nevertheless, a simulation study using a physiologically based pharmacokinetic model predicted that the effect of rosuvastatin on the pharmacokinetic profile of ELT in vivo would be minimal. On the other hand, ELT potently inhibited uptake of rosuvastatin by OATP1B1 and human hepatocytes, with an IC 50 of 0.1 mM. However, the results of the simulation study indicated that inhibition of OATP1B1 by ELT can only partially explain the clinically observed interaction with rosuvastatin. ELT also inhibited transcellular transport of rosuvastatin in MDCKII cells stably expressing breast cancer resistance protein (BCRP), and was found to be a substrate of BCRP. The interaction of ELT with rosuvastatin can be almost quantitatively explained on the assumption that intestinal secretion of rosuvastatin is essentially completely inhibited by ELT. These results suggest that BCRP in small intestine may be the major target for interaction between ELT and rosuvastatin in humans.

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“…This membrane-associated scaffold protein contains several PDZ domains, which interact with specific C-terminal PDZ-binding motifs of other proteins, thereby coordinating membrane localization, signal transduction, and posttranslational modifications of its targets (21). Functional interaction of PDZK1 has been shown for uptake transporters URAT1 and OAT4 as well as for efflux transporters NPT1 and ABCG2, thereby suggesting that PDZK1 stabilizes the apical urate transporter network (1,10,27,40).…”

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confidence: 99%

Transcriptional regulation of urate transportosome member SLC2A9 by nuclear receptor HNF4α

Prestin

Wolf

Strohbach

et al. 2014

American Journal of Physiology-Renal Physiology

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handling of urate is realized by a network of uptake and efflux transporters, including members of drug transporter families such as solute carrier proteins and ATP-binding cassette transporters. Solute carrier family 2, member 9 (SLC2A9), is one key factor of this so called "urate transportosome." The aim of the present study was to understand the transcriptional regulation of SLC2A9 and to test whether identified factors might contribute to a coordinated transcriptional regulation of the transporters involved in urate handling. In silico analysis and cell-based reporter gene assays identified a hepatocyte nuclear factor (HNF)4␣-binding site in the promoter of SLC2A9 isoform 1, whose activity was enhanced by transient HNF4␣ overexpression, whereas mutation of the binding site diminished activation. HNF4␣ overexpression induced endogenous SLC2A9 expression in vitro. The in vivo role of HNF4␣ in the modulation of renal SLC2A9 gene expression was supported by findings of quantitative real-time RT-PCR analyses and chromatin immunoprecipitation assays. Indeed, mRNA expression of SLC2A9 and HNF4␣ in human kidney samples was significantly correlated. We also showed that in renal clear cell carcinoma, downregulation of HNF4␣ mRNA and protein expression was associated with a significant decline in expression of the transporter. Taken together, our data suggest that nuclear receptor family member HNF4␣ contributes to the transcriptional regulation of SLC2A9 isoform 1. Since HNF4␣ has previously been assumed to be a modulator of several urate transporters, our findings support the notion that there could be a transcriptional network providing synchronized regulation of the functional network of the urate transportosome.

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PDZK1 Regulates Breast Cancer Resistance Protein in Small Intestine

Cited by 43 publications

References 36 publications

Common Variant of PDZK1, Adaptor Protein Gene of Urate Transporters, is Not Associated with Gout

Common Variant of PDZK1, Adaptor Protein Gene of Urate Transporters, is Not Associated with Gout

Interaction of Novel Platelet-Increasing Agent Eltrombopag with Rosuvastatin via Breast Cancer Resistance Protein in Humans

Transcriptional regulation of urate transportosome member SLC2A9 by nuclear receptor HNF4α

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