Reverse Translational Research of <i>ABCG2</i> (BCRP) in Human Disease and Drug Response

Brackman, Deanna J.; Giacomini, Kathleen M.

doi:10.1002/cpt.903

Cited by 26 publications

(27 citation statements)

References 69 publications

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“…Furthermore, besides changes in dietary intake and nutritional requirement, ontogeny of renal transporters can alter the disposition of endogenous compounds, suggesting important developmental roles for these renal transporters. Both BCRP and URAT1 are thought to play a clear role in uric acid (UA) homeostasis . It was previously reported that the fractional excretion of UA (FEUA; the % of filtered UA not reabsorbed by the tubules), was 30–40% in term newborns < 5 days old, which then decreased to 8–10% in children of 3 years old .…”

Section: Discussionmentioning

confidence: 99%

“…Both BCRP and URAT1 are thought to play a clear role in uric acid (UA) homeostasis. 23,24 It was previously reported that the fractional excretion of UA (FEUA; the % of filtered UA not reabsorbed by the tubules), was 30-40% in term newborns < 5 days old, which then decreased to 8-10% in children of 3 years old. [25][26][27] Our transporter maturation data, in addition to age-related physiological changes (e.g., urinary acidification and concentration ability), may explain this observation: the decreasing BCRP mRNA expression from birth is accompanied by an increased expression of URAT1, a reabsorptive transporter, from birth until childhood, resulting in a net decrease in UA excretion.…”

Section: Transporter-dependent Maturation Patterns During the Earliesmentioning

confidence: 99%

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A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

Cheung

Groen

Spaans

et al. 2019

Clin Pharma and Therapeutics

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136

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Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real-time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p-glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age. Protein levels of multidrug and toxin extrusion transporter 2-K and breast cancer resistance protein showed no difference from newborns to adults, despite age-related changes in mRNA expression. Multidrug and toxin extrusion transporter 1, glucose transporter 2, multidrug resistance-associated protein 2, multidrug resistance-associated protein 4 (MRP4), and PXR expression levels were stable. Using immunohistochemistry, we found that MRP4 localization in pediatric samples was similar to that in adult samples. Collectively, our study revealed that renal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of substrates may change with age.

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Section: Discussionmentioning

confidence: 99%

Section: Transporter-dependent Maturation Patterns During the Earliesmentioning

confidence: 99%

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

Cheung

Groen

Spaans

et al. 2019

Clin Pharma and Therapeutics

Self Cite

136

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“…The majority of these genes function as tumor suppressors in different cancers. We found genes including HP1α, multidrug resistance gene ABCG2 [ 44 ], ANGPTL4, APC2, u-PA, JPH3, TLN1, and TERT, and signaling pathways involved in cellular differentiation, growth, adhesion, angiogenesis, hypoxia, apoptotic, canonical Wnt, and toll-like receptor signaling pathways were differentially expressed or significantly altered in lung cancer cells upon G9a knockdown. A study showed that G9a knockdown in breast cancer changed a cohort of genes involved in EMT, a phenotypic conversion linked with metastasis [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting histone methyltransferase G9a inhibits growth and Wnt signaling pathway by epigenetically regulating HP1α and APC2 gene expression in non-small cell lung cancer

et al. 2018

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BackgroundDysregulated histone methyltransferase G9a may represent a potential cancer therapeutic target. The roles of G9a in tumorigenesis and therapeutics are not well understood in non-small cell lung cancer (NSCLC). Here we investigated the impact of G9a on tumor growth and signaling pathways in NSCLC.MethodsImmunohistochemistry analyzed G9a expression in NSCLC tissues. Both siRNA and selective inhibitor were used to target G9a. The impact of targeting G9a on key genes, signaling pathways and growth were investigated in NSCLC cells by RNA sequencing analysis, rescue experiments, and xenograft models.ResultsOverexpression of G9a (≥ 5% of cancer cells showing positive staining) was found in 43.2% of 213 NSCLC tissues. Multiple tumor-associated genes including HP1α, APC2 are differentially expressed; and signaling pathways involved in cellular growth, adhesion, angiogenesis, hypoxia, apoptosis, and canonical Wnt signaling pathways are significantly altered in A549, H1299, and H1975 cells upon G9a knockdown. Additionally, targeting G9a by siRNA-mediated knockdown or by a selective G9a inhibitor UNC0638 significantly inhibited tumor growth, and dramatically suppressed Wnt signaling pathway in vitro and in vivo. Furthermore, we showed that treatment with UNC0638 restores the expression of APC2 expression in these cells through promoter demethylation. Restoring HP1α and silencing APC2 respectively attenuated the inhibitory effects on cell proliferation and Wnt signaling pathway in cancer cells in which G9a was silenced or suppressed.ConclusionsThese findings demonstrate that overexpressed G9a represents a promising therapeutic target, and targeting G9a potentially suppresses growth and Wnt signaling pathway partially through down-regulating HP1α and epigenetically restoring these tumor suppressors such as APC2 that are silenced in NSCLC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0896-8) contains supplementary material, which is available to authorized users.

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“…Although post-transcriptional and translational regulation are involved in BCRP regulation [10][11][12], it is well documented that the regulation of BCRP mainly occurs at the transcriptional level [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Identification of Functional Transcriptional Binding Sites within Chicken Abcg2 Gene Promoter and Screening Its Regulators

Zhang

Huang

et al. 2020

Genes

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Breast cancer resistance protein (BCRP), an ATP-binding cassette (ABC) half transporter encoded by the Abcg2 gene, is reported to influence the pharmacokinetics of substrate drugs during clinical therapy. The aim of this study was to clarify the mechanisms that regulate the transcription of the chicken Abcg2 gene through cloning and characterization of its promoter region. Results showed that the Abcg2 gene is transcribed by a TATA-less promoter with several putative Sp1 sites upstream from two putative CpG islands. A luciferase reporter assay conducted both in chicken leghorn male hepatoma (LMH) cells and chicken primary hepatocytes mapped a basal promoter to nucleotides −110 to +30, which is responsible for the constitutive expression of Abcg2. The 5′-region upstream of the basal promoter was characterized by both positive and negative regulatory domains. Further, using the cell-based reporter gene assay combined with RT-PCR and drug accumulation analysis, we found that four xenobiotics, daidzein, clotrimazole, ivermectin, and lipopolysaccharide (LPS), influence the expression and function of BCRP through significant regulation of the Abcg2 gene promoter. Interaction sites with the Abcg2 gene promoter of these four selected regulators were clarified by progressive deletions and mutation assays. This study shed some light on the regulatory mechanisms involved in chicken Abcg2 gene expression and the results may have far-reaching significance regarding the usage and development of veterinary drugs.

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Reverse Translational Research of ABCG2 (BCRP) in Human Disease and Drug Response

Cited by 26 publications

References 69 publications

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

Targeting histone methyltransferase G9a inhibits growth and Wnt signaling pathway by epigenetically regulating HP1α and APC2 gene expression in non-small cell lung cancer

Identification of Functional Transcriptional Binding Sites within Chicken Abcg2 Gene Promoter and Screening Its Regulators

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