P Borst

..We concluded that the linear DNAs 'crawl like snakes head on through the gel'. This paper reviews some of the early experiments preceding the introduction of ethidium agarose gel electrophoresis...

..The physiological function of MRP4 and 5 remains to be found...

..We briefly review how ABC transporters in general, and MRPs in particular, could affect the disposition and cellular accumulation of antiviral compounds...

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..We delineate alternative approaches that should be able to yield predictive markers that can be used for optimizing patient treatment...

..Taken together with the mouse mammary tumor data, these observations raise the possibility that proliferating cells have no readily available mechanism to escape from cisplatin DNA damage once their HR is irreversibly inactivated...

..Instead, we have found a role for MRP3 in the cellular export of drug-glucuronide conjugates. We discuss problems in extrapolating results obtained for murine MRPs...

..The hypothesis implies that the symptoms of PXE can be prevented or mitigated by providing patients (intravenously) with a form of plasma vitamin K (precursor) that can be used by peripheral tissues...

..We conclude that there is no unambiguous proof for co-transport of two different ligands by MRPs, but that cross-stimulated transport can explain the published data...

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..The possibility that such a structure might explain monoallelic expression in other multigene systems is discussed here...

..c) A rapidly increasing number of ABC transporters are found to play a role in lipid transport. Defects in each of these transporters are involved in human inborn or acquired diseases...

..This mechanism can be accompanied by other resistance mechanisms, such as reduced topo II alpha mRNA in case of doxorubicin selection...

..This implies that ethacrynic acid may modulate drug resistance of tumor cells not only by inhibiting glutathione S-transferase activity, but also by inhibiting the export of drug conjugates from the cell by MRP...

..A third example, the ABC transporter involved in the import of long-chain fatty acids into peroxisomes, is discussed in the chapter by Hettema and Tabak in this volume...

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..Our results suggest that this ubiquitous GS-X pump is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible...

..The promoter region contains several consensus sequences where known or putative liver-specific (C/EBP, HNF5) or lymphoid specific (Pu.1, ets-1) transcription factors may bind...

..Unexpectedly, export of the organic anion calcein by MDCKII-MRP1 and MDCKII-MRP2 cells is stimulated by Pluronic L61, probably because it relieves the block on entry of calcein AM into the cell by endogenous MDR1 Pgp...

..We discuss the possible function of MRP3 in (hepatic) physiology and its potential contribution to drug resistance of cancer cells...

..Our results indicate that Mrp1 helps to limit tissue distribution of certain drugs and contributes to the blood-CSF drug-permeability barrier...

..We conclude that cMOAT is a 5'-adenosine triphosphate binding cassette transporter that potentially might be involved in drug resistance in mammalian cells...

..mdr1a/1b (-/-) mice should provide a useful model system to further test the pharmacological roles of the drug-transporting P-gps and to analyze the specificity and effectivity of P-gp-blocking drugs...

..We speculate that MRP5 might play a role in some cases of unexplained resistance to thiopurines in acute lymphoblastic leukemia and/or to antiretroviral nucleoside analogs in HIV-infected patients...

..Our results emphasize the need for gene-specific blocks in gene expression to define which transporter contributes to resistance in each resistant cell line...

..The physiologic functions of the other MRPs are not known. Whether long-term inhibition of MRPs in humans can be tolerated (assuming that suitable inhibitors will be found) remains to be determined...

..Even though etoposide glucuronide is an excellent substrate for MRP3, this compound is not involved in the etoposide resistance of our MRP3 cells, as these cells extrude unmodified etoposide rather than etoposide glucuronide...

..We conclude that mouse erythrocytes contain at least two transport systems for PGA2-GS. One of these is mrp1; the other one has not been identified yet, but can be inhibited by methotrexate and cAMP...

..The J-binding proteins show 43-63% identity and are unlike any known protein. The discovery of a J-binding protein suggests that J, like methylated cytosine in higher eukaryotes, functions via a protein intermediate...

..We discuss how PC might reach the canalicular membrane of the hepatocyte for secretion into the bile, if not by Pc-tp...

..Recent experiments with polarized cells support the idea that drug-transporting P-glycoproteins act by flipping drugs from the inner to the outer leaflet of the plasma membrane...

..Our results indicate that specific inhibitors of MRP1 used to reverse MDR, in combination with carcinostatic drugs transported by MRP1, might lead to drug-induced mucositis, (temporary) infertility, and diabetes insipidus...

..Our results suggest that MRP6 does not play a role in the resistance of the resistant cells analyzed, and that MRP6/ARA is only coamplified with MRP1 because of its location immediately next to it on the same chromosome...

..We speculate that these effects are mediated by the packaging of J-containing DNA into a condensed chromatin structure...

..The excretion of cholesterol is not tightly coupled to the excretion of phospholipids in these mice, because a very low phospholipid excretion level is sufficient to give almost wild-type cholesterol excretion into the bile...

..The MDR1 Pgp can transport drugs; the murine homologue of MDR3, mdr2, was recently shown by us to be involved in transport of the phospholipid phosphatidylcholine (lecithin) into bile...

..However, at high sulfinpyrazone concentrations this compound is transported without GSH. Models of MRP action are discussed that could explain these results...

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..For some drugs, this leads to dramatically increased toxicity, indicating that P-glycoprotein inhibitors should be used with caution in patients...

..We conclude that mrp1(-/-) mice are resistant against pneumococcal pneumonia by a mechanism that involves increased release of LTB(4). These results identify mrp1 as a novel target for adjunctive therapy in pneumonia...

..The fact that we pick up these normally infrequent deletions, indicates that inactivation of the old VSG expression site could be rate limiting during switching in our strain of T. brucei...

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..Our results confirm the central role of the mdr1 (pgp1) gene in MDR and suggest that different cross-resistance patterns are not due to differential expression of different P-glycoprotein genes...

..80% of the amino acids are conserved between the products of mdr1 and mdr3. Although the function of mdr3 is not yet known, its high homology with mdr1 suggests that it also encodes an efflux pump with broad specificity...

..Our results show that all major thiopurine monophosphates important in the efficacy of mercaptopurine treatment are transported by MRP4 and MRP5, although the substrate specificity of the two transporters differs in detail...

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..This genomic location at chromosome ends not only allows easy exchange of VSG gene cassettes using various mechanisms of DNA recombination but also appears to play a role in VSG gene expression site control...

..These results encourage further research on the development of a clinically useful oral formulation of paclitaxel...

..The assay we used, which measures DNA breaks as an end point of topo II activity, could be a good candidate...

..In the present study, we have isolated the human homologue of rat cmoat, human cMOAT, and analyzed the corresponding cDNA from fibroblasts of a DJS patient for mutations. Our results show that a mutation in this gene is the cause of DJS...

..Analysis of the consequences of Pgp blockade has been facilitated by the generation of mice with disrupted mdr1a genes [mdr1a(-/-)]...

..We conclude that JBP is a structure-specific DNA-binding protein. The significance of these results in relation to the biological role and mechanism of action of J modification in kinetoplastids is discussed...

..We conclude that JBP2, like JBP1, is in all probability a thymidine hydroxylase involved in the biosynthesis of base J...

..hSMUG1 also reduces the J content of the trypanosome DNA. This work supports the idea that HOMeUra is a precursor of J, freely accessible to a DNA glycosylase...

..We conclude that JBP is able to activate the thymine modification enzymes to introduce additional J in regions of DNA already containing a basal level of J. We propose that JBP is a novel DNA modification maintenance protein...

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..In addition to adult liver, high levels of PC-TP RNA were also found in kidney and testis. The prominent presence of PC-TP in developing and adult liver is compatible with its proposed role in bile formation...

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..We propose that JBP1 is a thymidine hydroxylase responsible for the local amplification of J inserted by JBP2, another putative thymidine hydroxylase...

..Because of its high sensitivity, it may also be useful for the detection of the low amounts of HOMedU resulting from oxidative damage of DNA...

..These results may explain a range of pharmacological interactions observed between various drugs in patients...

..This review summarizes recent work on the mechanism of site switching and on the way inactive expression sites are kept silent...

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..Whereas, a "silent" ES shows a low level of expression of promoter proximal sequences, the level of activation can be reversibly increased, leading to partially activated ESs...

..We find that olaparib substantially increases topotecan toxicity in this model, and we suggest that this might also happen in humans...

..We propose that these amplicons have arisen by a template switch inside a DNA replication fork involving the inverted DNA repeats and helped by the gene targeting...

..brucei, Trypanosoma equiperdum and Trypanoplasma borreli. Our results suggest that J is a telomeric base modification, recruited for other (unknown) functions in some kinetoplastids and Euglena...

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..The presence of J in DNA does not require a specific modification of the BER system, as this base is not recognized by any known DNA glycosylase...

..Our data show the usefulness of realistic preclinical models to characterize levels of Mdr1 gene expression that are sufficient to cause resistance...

..4, is efficiently transported by BCRP at pH 6.0, whereas we did not detect active transport at pH 7.4. We conclude that BCRP transports substrate drugs more efficiently at low pH, independent of the dissociation status of the substrate...

..Our results underline the promise of these mouse tumors for the study of tumor-initiating cells and of drug therapy of human cancer...

..These results suggest that the TfR flagellar pocket retention mechanism is easily saturated and that control of the expression level is critical to maintain the restricted surface distribution of the receptor...

..Our findings suggest a physiological role for MRP1 and MRP4 in DHEAS transport and an involvement of MRP4 in transport of conjugated steroids and bile acids...

..Our results illustrate the striking genetic flexibility of trypanosomes...

..The CpG-rich sequences marking the 5' ends of both genes are hypomethylated to different extents in different cell lines. Hypomethylation roughly correlates with transcriptional activity...

..These findings may be of potential clinical relevance when considering the drug treatment regimens for these tumor types...

..Our results suggest that a high-affinity Tf-R not only ensures efficient Tf uptake, but is also required to allow sufficient iron uptake by the trypanosome in the presence of anti-Tf-R antibodies...

..The relative contribution of ABCC4/Abcc4 and ABCG2/Abcg2 in cGMP transport was confirmed with a new inhibitor of ABCC4 transport, the protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride...

..Multidrug Resistance Protein 3 (MRP3) transports bile salts and glucuronide conjugates in vitro and is postulated to protect the liver in cholestasis. Whether the absence of Mrp3 affects these processes in vivo is tested...

..These results show the potential of MRP5 to mediate transport of (anti)folates and contribute to resistance against antifolate drugs...

..The pharamacokinetics of injected morphine-glucuronides are altered as well in the absence of Mrp3, and this results in a decreased antinociceptive potency of injected morphine-6-glucuronide...

..Our results show that murine Mrp2 and Mrp3 provide alternative routes for the excretion of a glucuronidated substrate from the liver in vivo...

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..In HEK-293 cells, it is predominantly localized in the endoplasmic reticulum. We have been unable to demonstrate transport by MRP9 of substrates transported by other MRPs, such as drug conjugates and other organic anions...

..Together, these data suggest that MRP4 can release prostaglandins from cells, and that, in addition to inhibiting prostaglandin synthesis, some nonsteroidal antiinflammatory drugs might also act by inhibiting this release...

..We propose that MRP2 contains two similar but nonidentical ligand binding sites: one site from which substrate is transported and a second site that regulates the affinity of the transport site for the substrate...

..The profound effects of ATP-binding cassette transporters on the disposal of resveratrol may be representative for the handling of several other polyphenols of dietary origin...

..This flexibility is made possible by the promoter-proximal position of the two genes in the variant surface glycoprotein expression site...

..These results strongly suggest that the affinity of MRP4 and MRP5 for nucleotide-based substrates is low...

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..v. MTX in wild-type mice. The conclusion is as follows: benzimidazoles differentially affect transport of MTX mediated by BCRP and MRP2. Competition for BCRP may explain the clinical interaction between MTX and benzimidazoles...

..Therefore, the 50 bp repeat arrays appear to be the boundary of the regulated expression site domain...

..Unexpected conservation of sequences, including pseudogenes, indicates that the multiple ESs could have arisen through a relatively recent amplification of a single ES...

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