Functional analysis of chimeric genes obtained by exchanging homologous domains of the mouse mdr1 and mdr2 genes.

These results suggest that the functional differences detected between mdr1 and mdr2 in our transfection assay reside within the predicted TM domains

E Buschman; P Gros

2015

Scholarcy highlights

  • A fufl-length cDNA clone for the mouse mdrl gene can confer multidrug resistance when introduced by transfection into otherwise drug-sensitive cells
  • To identify the domains of mdrl which are essential for multidrug resistance and which may be functionally distinct in mdr2, we have constructed chimeric cDNA molecules in which discrete domains of mdr2 have been introduced into the homologous region of mdrl and analyzed these chimeras for their capacity to transfer drug resistance
  • These results suggest that the functional differences detected between mdrl and mdr2 in our transfection assay reside within the predicted TM domains
  • Analysis of the mouse mdr gene transcripts in normal tissues shows that expression of the three genes is controlled in a tissue-specific manner . mdrl is constitutively expressed in adrenal glands and kidney and is induced at high levels in the endometrial glands of the pregnant uterus . mdr2 is primarily expressed in liver and muscle, and mdr3 is primarily expressed in intestine and lung
  • The structural similarities and functional differences detected between mouse mdrl, mdr2, and mdr3 in transfection experiments together with the specific tissue distribution of their mRNAs suggest that mdr genes code for membrane proteins which may participate in similar transport functions of perhaps distinct substrates
  • These include two series of six predicted TM segments, two predicted nucleotide-binding sites, and the highly sequence divergent linker domain. Despite this high sequence homology, the two genes are functionally distinct in that only mdrl is capable of conferring multidrug resistance when transfected into otherwise drug-sensitive LR73 hamster cells
  • Our analysis of mdrl-mdr2 chimeras indicates that both predicted ATP-binding sites and the linker domain of mdr2 can complement the drug resistance phenotype encoded by mdrl, suggesting that these regions encode common structural or functional aspects of these two proteins

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