Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin–Johnson syndrome

Tsujii, Hiroyuki; König, Jörg; Rost, Daniel; Stöckel, Birgit; Leuschner, U.; Keppler, Dietrich

doi:10.1016/s0016-5085(99)70459-2

Cited by 138 publications

(94 citation statements)

References 17 publications

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“…ABCC2 is structurally and functionally very distinct from MDR1 P-glycoprotein (ABCB1), which belongs to a different subfamily of ABC transporters with which ABCC2 shares only about 26% amino acid sequence identity. The human ABCC2 gene is located on chromosome 10q24 [165], spans about 65 kilobase pairs, and consists of 32 exons with a high proportion of class 0 introns [168,170].…”

Section: Molecular Characterization Of Abcc2mentioning

confidence: 99%

“…Clofibrate, which is a ligand for the peroxisome proliferator-activated receptor α (PPARα, NR1C1 [59]), also decreased rat Abcc2 protein levels by posttranscriptional mechanisms [68]. [72,82,134,170]. This syndrome is an autosomal, recessively inherited disorder characterized by conjugated hyperbilirubinemia (i.e., increased concentration of bilirubin glucuronosides in blood) and deposition of a dark pigment in hepatocytes, so that the liver of an affected individual appears dark blue or black [31, 145,158].…”

Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning

confidence: 99%

“…Premature stop codons may cause rapid degradation of the mutated ABCC2 mRNA by nonsense-mediated decay, a mechanism which cotranslationally recognizes when a stop codon precedes the last splice-site [167], thus leading to the absence of the ABCC2 protein in some cases of Dubin-Johnson syndrome. In fact, a truncated ABCC2 protein has not been detected so far [134,170]. Other Dubin-Johnson syndrome-associated sequence variants lead to deficient maturation and impaired sorting of the ABCC2 protein or to an apically localized, but functionally inactive, ABCC2 protein [47, 79,80,117] (Table 3).…”

Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning

confidence: 99%

See 2 more Smart Citations

The apical conjugate efflux pump ABCC2 (MRP2)

Nies

Keppler

2006

Pflugers Arch - Eur J Physiol

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352

255

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ABCC2 is a member of the multidrug resistance protein subfamily localized exclusively to the apical membrane domain of polarized cells, such as hepatocytes, renal proximal tubule epithelia, and intestinal epithelia. This localization supports the function of ABCC2 in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly in the unidirectional efflux of substances conjugated with glutathione, glucuronate, or sulfate, as exemplified by leukotriene C 4 , bilirubin glucuronosides, and some steroid sulfates. The hepatic ABCC2 pump contributes to the driving forces of bile flow. Acquired or hereditary deficiency of ABCC2, the latter known as Dubin-Johnson syndrome in humans, causes an increased concentration of bilirubin glucuronosides in blood because of their efflux from hepatocytes via the basolateral ABCC3, which compensates for the deficiency in ABCC2-mediated apical efflux. In this article we provide an overview on the molecular characteristics of ABCC2 and its expression in various tissues and species. We discuss the transcriptional and posttranscriptional regulation of ABCC2 and review approaches to the functional analysis providing information on its substrate specificity. A comprehensive list of sequence variants in the human ABCC2 gene summarizes predicted and proven functional consequences, including variants leading to Dubin-Johnson syndrome. Keywords

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Section: Molecular Characterization Of Abcc2mentioning

confidence: 99%

Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning

confidence: 99%

Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning

confidence: 99%

See 1 more Smart Citation

The apical conjugate efflux pump ABCC2 (MRP2)

Nies

Keppler

2006

Pflugers Arch - Eur J Physiol

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352

255

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“…The expression of Mrp2 is down-regulated in these animal models of cholestasis through both transcriptional and post-transcriptional events (30), and the expression of Mrp3 was induced (31,32). In humans, Dubin-Johnson syndrome, an autosomal recessive disease, is characterized by a defect in the transfer of endogenous and exogenous anionic conjugates from hepatocytes into the bile because of mutations in MRP2 gene (33)(34)(35)(36). It was reported that MRP3 was up-regulated in a patient with Dubin-Johnson syndrome (27).…”

mentioning

confidence: 99%

Enhanced Expression of the Human Multidrug Resistance Protein 3 by Bile Salt in Human Enterocytes

Inokuchi¹,

Hinoshita²,

Iwamoto³

et al. 2001

Journal of Biological Chemistry

105

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The enterohepatic circulation is essential for the maintenance of bile acids and cholesterol homeostasis. The ileal bile acid transporter on the apical membrane of enterocytes mediates the intestinal uptake of bile salts, but little is known about the bile salt secretion from the basolateral membrane of enterocytes into blood. In the basolateral membrane of enterocytes, an ATP-binding cassette transporter, multidrug resistance protein 3 (MRP3), is expressed, which has the ability to transport bile salts. We hypothesized that MRP3 might play a role in the enterohepatic circulation of bile salts by transporting them from enterocytes into circulating blood through the up-regulation of MRP3 expression, so we investigated the transcriptional control of MRP3 in response to bile salts. MRP3 mRNA levels were increased about 3-fold in human colon cells by chenodeoxycholic acid (CDCA), in a dose-and time-dependent manner. In the promoter assay, the promoter activity of MRP3 was increased about 3-fold over the basal promoter activity when treated with CDCA, and the putative bile salt-responsive elements exist in the region ؊229/؊138 including two ␣-1 fetoprotein transcription factor (FTF)-like elements. Constructs with a specific mutation in the consensus sequence of FTF elements showed no increase in basal transcriptional activity following CDCA treatment. In electrophoretic mobility shift assay with nuclear extracts, specific binding of FTF to FTF-like elements was observed when treated with CDCA. The expression of FTF mRNA levels were also markedly enhanced in response to CDCA, and overexpression of FTF specifically activated the MRP3 promoter activity about 4-fold over the basal promoter activity. FTF thus might play a key role not only in the bile salt synthetic pathway in hepatocytes but also in the bile salt excretion pathway in enterocytes through the regulation of MRP3 expression. MRP3 may contribute as a plausible bile salt-exporting transporter to the enterohepatic circulation of bile salts.

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“…The ABCC2 gene, also known as canalicular multispecific organic anion transporter (cMOAT), was initially cloned from the rat liver (Buchler et al, 1996;Paulusma et al, 1996) and subsequently cloned from the human liver, and the first mutations of the ABCC2 gene in patients with DJS were detected in 1997 (Paulusma et al, 1997). The human ABCC2 gene, which has been localized to chromosome 10q24 (van Kuijck et al, 1997), spans about 45 kilobases and contains 32 exons ranging in size from 56 to 255 base pairs (Tsujii et al, 1999). So far, nine kinds of mutations of the ABCC2 gene have been reported (Kajihara et al, 1998;Tsujii et al, 1999;Toh et al, 1999;Mor-Cohen et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

A new mutation of the ATP-binding cassette, sub-family C, member 2 (ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome.

Tate

Suzuki

et al. 2002

Genes Genet. Syst.

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Dubin-Johnson syndrome (DJS) is an inherited disorder characterized by conjugated hyperbilirubinemia and is caused by mutations of the canalicular multispecific organic anion transporter (cMOAT)/ multidrug resistance protein 2 (MRP2)/ ATP-binding cassette, sub-family C, member 2 (ABCC2) gene. The ABCC2 protein is located in the apical membrane of hepatocytes, and known mutations of this gene cause impaired maturation and trafficking of the mutated protein from the endoplasmic reticulum (ER) to the Golgi complex. We have characterized the ABCC2 gene in a Japanese DJS patient by polymerase chain reaction and DNA sequencing, resulting in the identification of two mutations. One mutation, 1815+2 (T>A) in the splice donor site of intron 13, has already been reported. However, we have identified a novel nonsense mutation consisting of a (C>T) transition at nucleotide 3928 in exon 28.

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Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin–Johnson syndrome

Cited by 138 publications

References 17 publications

The apical conjugate efflux pump ABCC2 (MRP2)

The apical conjugate efflux pump ABCC2 (MRP2)

Enhanced Expression of the Human Multidrug Resistance Protein 3 by Bile Salt in Human Enterocytes

A new mutation of the ATP-binding cassette, sub-family C, member 2 (ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome.

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