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Two closely related but functionally distinct P-glycoprotein isoforms are encoded by the murine multidrug-resistance genes mdr1a and mdr1b. In a series of independently selected multidrug-resistant (MDR) J774.2 cell lines, mdr gene amplification and/or overexpression and overproduction of either the mdr1a or mdr1b products, or both gene products, correlates with the MDR phenotype. To investigate the possibility that mutations in the promoter regions of the mdr1a or mdr1b genes could influence their differential expression, mdr promoter-specific probes were used to detect and map potential structural alterations. An unusual structural rearrangement was found in the 5'-region of the amplified mdr1a allele in J7.T1, a cell line selected with taxol. To characterize this rearrangement, the regulatory regions of the mdr1a and mdr1b genes were analyzed. Whereas no gross structural alterations were detected by Southern blot hybridization using the mdr1b promoter probe, a novel amplified EcoRI fragment was detected by the mdr1a promoter probe. To determine the precise nature of this mutation, an mdr1a 5'-genomic clone was isolated from J7.T1 cells. Sequence analysis revealed an unusual DNA rearrangement consisting of the mdr1b gene, from its fourth intron toward its 3'-end, upstream of an intact mdr1a promoter on the amplified allele. We propose that this event occurred by an unequal sister chromatid exchange that was mediated by LINE-1 repetitive elements.  相似文献   

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P-glycoprotein is an integral membrane protein that is overproduced in multidrug-resistant cells. It is likely to function as an energy-dependent drug efflux pump to maintain intracellular drug concentrations below cytotoxic levels. Individually isolated multidrug-resistant murine cell lines, J7.V1-1 and J7.V3-1, overproduce P-glycoproteins encoded by the mdr1b and mdr1a genes, respectively. The transport properties of these cell lines and the drug binding characteristics of their P-glycoproteins have been compared. It is concluded that 1) the mdr1a gene product is a more efficient efflux pump than the mdr1b gene product, and 2) whereas a single class of vinblastine binding sites is present in J7.V1-1 membrane vesicles, there appears to be two classes of such sites in J7.V3-1 membrane vesicles. The effects of verapamil and progesterone, two compounds that are known to interact with P-glycoprotein, have been analyzed in the two cell lines. Progesterone inhibited drug binding and efflux and increased drug sensitivity to vinblastine with more potency in J7.V1-1 cells than in J7.V3-1 cells. It is concluded that progesterone, but not verapamil, can be used to differentiate the two mdr gene products in the mouse.  相似文献   

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In multidrug-resistant murine J774.2 cells, the mdr1a and mdr1b genes encode the 120- and 125-kDa P-glycoprotein precursors, respectively (Hsu, S. I., Lothstein, L., and Horwitz, S.B. (1989) J. Biol. Chem. 264, 12053-12062). It is shown here that a J774.2 cell line selected for vinblastine resistance (J7.V3) switched from the 125- to 120-kDa precursor when cells that were maintained in 20 nM vinblastine were grown in 40 nM vinblastine for 20 months. The rate of switching was accelerated by growing cells in higher levels of vinblastine. These findings suggest that cells which express mdr1a have a selective growth advantage compared to cells which express mdr1b. Consistent with this hypothesis, the switching event that occurs in cells maintained at 40 nM vinblastine was correlated with 3.5-5-fold higher levels of resistance to vinblastine, taxol, and doxorubicin in the absence of any detectable increase in the amount of immunoreactive P-glycoprotein. These findings suggest that P-glycoproteins derived from mdr1a and mdr1b are functionally distinct.  相似文献   

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Two vinblastine-resistant sublines of the murine macrophage-like cell line J774.2, J7.V1-1 and J7.V3-1, overproduce unique forms of P-glycoprotein that are encoded by distinct mdr genes, mdr1b and mdr1a, respectively. Degradation rates of the two P-glycoprotein isoforms were measured by immunoprecipitation of P-glycoprotein. The half-life of immunoprecipitable P-glycoprotein from J7.V1-1 cells was 16.8 +/- 0.5 hours and from J7.V3-1 cells, 17.4 +/- 0.5 hours. This rate was not influenced by the presence of vinblastine in the growth medium. The data indicate that P-glycoproteins derived from distinct genes have similar degradation rates.  相似文献   

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Molecular analysis of the yellow locus of Drosophila   总被引:18,自引:4,他引:14       下载免费PDF全文
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