The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues.

The gene responsible for multidrug resistance (mdr), which encodes the P-glycoprotein, is a member of a multigene family. We have identified distinct mdr gene transcripts encoded by three separate mdr genes in the mouse. Expression levels of each mdr gene are dramatically different in various mouse tissues. Specific mdr RNA transcripts of approximately 4.5, 5, and 6 kilobases have been detected. Each of the mdr genes has a specific RNA transcript pattern. These results should be considered in relation to understanding the normal physiological function of the mdr multigene family.

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Identification of members of the P-glycoprotein multigene family.

Molecular and Cellular Biology ◽

10.1128/mcb.9.3.1224 ◽

1989 ◽

Vol 9 (3) ◽

pp. 1224-1232 ◽

Cited By ~ 146

Author(s):

W F Ng ◽

F Sarangi ◽

R L Zastawny ◽

L Veinot-Drebot ◽

V Ling

Keyword(s):

Multidrug Resistance ◽

Gene Duplication ◽

Gene Family ◽

Multigene Family ◽

Rhesus Monkeys ◽

Genomic Library ◽

Duplication Event ◽

Glycoprotein Gene ◽

P Glycoprotein ◽

Exon Probe

Overproduction of P-glycoprotein is intimately associated with multidrug resistance. This protein appears to be encoded by a multigene family. Thus, differential expression of different members of this family may contribute to the complexity of the multidrug resistance phenotype. Three lambda genomic clones isolated from a hamster genomic library represent different members of the hamster P-glycoprotein gene family. Using a highly conserved exon probe, we found that the hamster P-glycoprotein gene family consists of three genes. We also found that the P-glycoprotein gene family consists of three genes in mice but has only two genes in humans and rhesus monkeys. The hamster P-glycoprotein genes have similar exon-intron organizations within the 3' region encoding the cytoplasmic domains. We propose that the hamster P-glycoprotein gene family arose from gene duplication. The hamster pgp1 and pgp2 genes appear to be more closely related to each other than either gene is to the pgp3 gene. We speculate that the hamster pgp1 and pgp2 genes arose from a recent gene duplication event and that primates did not undergo this duplication and therefore contain only two P-glycoprotein genes.

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Changes in the nature of P-glycoprotein gene transcripts during the development of multidrug resistance in CHO cells.

Cell Biology International ◽

10.1006/cbir.1995.1005 ◽

1995 ◽

Vol 19 (1) ◽

pp. 35-42 ◽

Cited By ~ 2

Author(s):

S Vickers

Keyword(s):

Multidrug Resistance ◽

Cho Cells ◽

Glycoprotein Gene ◽

P Glycoprotein ◽

Gene Transcripts

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Physical mapping, amplification, and overexpression of the mouse mdr gene family in multidrug-resistant cells.

Molecular and Cellular Biology ◽

10.1128/mcb.10.4.1642 ◽

1990 ◽

Vol 10 (4) ◽

pp. 1642-1651 ◽

Cited By ~ 95

Author(s):

M Raymond ◽

E Rose ◽

D E Housman ◽

P Gros

Keyword(s):

Molecular Weight ◽

Multidrug Resistance ◽

Gene Family ◽

Cell Lines ◽

Gene Amplification ◽

Genomic Dna ◽

Multidrug Resistant ◽

Pulse Field ◽

P Glycoprotein ◽

Mdr Genes

The mouse mdr gene family consists of three distinct genes (mdr1, mdr2, and mdr3), for which we have isolated full-length cDNA clones. cDNA subfragments corresponding to discrete regions showing little sequence conservation among the three mdr genes were used as gene-specific DNA probes in hybridization experiments. Long-range mapping by pulse-field gel electrophoresis indicated that the three mdr genes are closely linked on a genomic DNA segment of approximately 625 kilobases. The gene order and direction of transcription of the three genes were determined and indicate the arrangement (5') mdr3 (3')-(5') mdr1 (3')-(3') mdr2 (5'). Southern blotting analyses of genomic DNA from a panel of independently derived multidrug-resistant cell lines identified mdr gene amplification in 10 of 12 cell lines studied. In individual cell lines showing gene amplification, the copy number of each of the three mdr genes was identical, suggesting that the three mdr genes became amplified as part of a single amplicon in these cells. Although increased expression of all three mdr genes was detected in 2 of 12 cell lines tested, multidrug resistance was associated in 10 of 12 lines with the independent overexpression of either mdr1 (7 of 12) or mdr3 (3 of 12) but not mdr2. mdr1 overexpression was consistently associated with gene amplification, while increased mdr3 expression was detected in certain cell lines that did not show gene amplification. Increased levels of mdr1 mRNA were linked to the overexpression of a P glycoprotein of apparent molecular weight 180,000 to 200,000, whereas increased mdr3 expression resulted in increased expression of a P glycoprotein of molecular weight 160,000 to 180,000. Our results suggest that at least two members of the mouse mdr gene family, mdr1 and mdr3, can independently confer multidrug resistance in the cell lines examined.

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Identification of members of the P-glycoprotein multigene family

Molecular and Cellular Biology ◽

10.1128/mcb.9.3.1224-1232.1989 ◽

1989 ◽

Vol 9 (3) ◽

pp. 1224-1232

Author(s):

W F Ng ◽

F Sarangi ◽

R L Zastawny ◽

L Veinot-Drebot ◽

V Ling

Keyword(s):

Multidrug Resistance ◽

Gene Duplication ◽

Gene Family ◽

Multigene Family ◽

Rhesus Monkeys ◽

Genomic Library ◽

Duplication Event ◽

Glycoprotein Gene ◽

P Glycoprotein ◽

Exon Probe

Overproduction of P-glycoprotein is intimately associated with multidrug resistance. This protein appears to be encoded by a multigene family. Thus, differential expression of different members of this family may contribute to the complexity of the multidrug resistance phenotype. Three lambda genomic clones isolated from a hamster genomic library represent different members of the hamster P-glycoprotein gene family. Using a highly conserved exon probe, we found that the hamster P-glycoprotein gene family consists of three genes. We also found that the P-glycoprotein gene family consists of three genes in mice but has only two genes in humans and rhesus monkeys. The hamster P-glycoprotein genes have similar exon-intron organizations within the 3' region encoding the cytoplasmic domains. We propose that the hamster P-glycoprotein gene family arose from gene duplication. The hamster pgp1 and pgp2 genes appear to be more closely related to each other than either gene is to the pgp3 gene. We speculate that the hamster pgp1 and pgp2 genes arose from a recent gene duplication event and that primates did not undergo this duplication and therefore contain only two P-glycoprotein genes.

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Physical mapping, amplification, and overexpression of the mouse mdr gene family in multidrug-resistant cells

Molecular and Cellular Biology ◽

10.1128/mcb.10.4.1642-1651.1990 ◽

1990 ◽

Vol 10 (4) ◽

pp. 1642-1651

Author(s):

M Raymond ◽

E Rose ◽

D E Housman ◽

P Gros

Keyword(s):

Molecular Weight ◽

Multidrug Resistance ◽

Gene Family ◽

Cell Lines ◽

Gene Amplification ◽

Genomic Dna ◽

Multidrug Resistant ◽

Pulse Field ◽

P Glycoprotein ◽

Mdr Genes

The mouse mdr gene family consists of three distinct genes (mdr1, mdr2, and mdr3), for which we have isolated full-length cDNA clones. cDNA subfragments corresponding to discrete regions showing little sequence conservation among the three mdr genes were used as gene-specific DNA probes in hybridization experiments. Long-range mapping by pulse-field gel electrophoresis indicated that the three mdr genes are closely linked on a genomic DNA segment of approximately 625 kilobases. The gene order and direction of transcription of the three genes were determined and indicate the arrangement (5') mdr3 (3')-(5') mdr1 (3')-(3') mdr2 (5'). Southern blotting analyses of genomic DNA from a panel of independently derived multidrug-resistant cell lines identified mdr gene amplification in 10 of 12 cell lines studied. In individual cell lines showing gene amplification, the copy number of each of the three mdr genes was identical, suggesting that the three mdr genes became amplified as part of a single amplicon in these cells. Although increased expression of all three mdr genes was detected in 2 of 12 cell lines tested, multidrug resistance was associated in 10 of 12 lines with the independent overexpression of either mdr1 (7 of 12) or mdr3 (3 of 12) but not mdr2. mdr1 overexpression was consistently associated with gene amplification, while increased mdr3 expression was detected in certain cell lines that did not show gene amplification. Increased levels of mdr1 mRNA were linked to the overexpression of a P glycoprotein of apparent molecular weight 180,000 to 200,000, whereas increased mdr3 expression resulted in increased expression of a P glycoprotein of molecular weight 160,000 to 180,000. Our results suggest that at least two members of the mouse mdr gene family, mdr1 and mdr3, can independently confer multidrug resistance in the cell lines examined.

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