DRUG-RESISTANCE AND P-GLYCOPROTEIN GENE AMPLIFICATION IN THE PROTOZOAN PARASITE LEISHMANIA

被引:79
作者
OUELLETTE, M
BORST, P
机构
[1] UNIV LAVAL, FAC MED, DEPT MICROBIOL, QUEBEC CITY G1K 7P4, QUEBEC, CANADA
[2] NETHERLANDS CANC INST, DIV MOLEC BIOL, 1066 CX AMSTERDAM, NETHERLANDS
关键词
GENE AMPLIFICATION; LEISHMANIA; RECOMBINATION; GLYCOPROTEIN; METHOTREXATE; DRUG RESISTANCE; P-GLYCOPROTEIN; INVERTED REPEATS; MULTIRESISTANCE;
D O I
10.1016/0923-2508(91)90089-S
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Amplification of the H circle is often associated with methotrexate (MTX) selection in Leishmania species. We have shown that the H circle of Leishmania tarentolae contains an open reading frame, ItpgpA, that has the attributes of P-glycoproteins (large plasma membrane proteins known to extrude lipophilic drugs from mammalian cells). H region amplification was also noted in some mutants selected for resistance to arsenite and vinblastine. Mutants having the complete 68-kb circles were cross-resistant to MTX, but two arsenite mutants having only part of the H region amplified, but including ItpgpA, were not cross-resistant to MTX. These results suggest that the putative determinant for MTX resistance present on the H circle is not ItpgpA. We have also determined how ItpgpA-containing plasmids were generated from the chromosomal copy. The H circle contains a 30-kb inverted duplication separated by two unique DNA segments. The corresponding H region of chromosomal DNA has only one copy of the duplicated DNA. We have shown that the two unique segments in chromosomal DNA are flanked by inverted repeats suggesting that H circles could be formed by a foldback mechanism (see fig. 2). Unexpectedly, a plasmid present in cells selected for arsenite resistance lacked part of the H region and the long inverted repeats. It appears to have been formed by intrachromosomal recombination between two P-glycoprotein genes, ItpgpA and ItpgPB, located adjacent to the H region. Our results show that under drug pressure, the same P-glycoprotein-encoding region in Leishmania may be amplified by very different mechanisms and yield different amplicons.
引用
收藏
页码:737 / 746
页数:10
相关论文
共 43 条
  • [41] CHLOROQUINE RESISTANCE NOT LINKED TO MDR-LIKE GENES IN A PLASMODIUM-FALCIPARUM CROSS
    WELLEMS, TE
    PANTON, LJ
    GLUZMAN, IY
    DOROSARIO, VE
    GWADZ, RW
    WALKERJONAH, A
    KROGSTAD, DJ
    [J]. NATURE, 1990, 345 (6272) : 253 - 255
  • [42] WHITE TC, 1988, J BIOL CHEM, V263, P16977
  • [43] AMPLIFICATION OF A GENE RELATED TO MAMMALIAN MDR GENES IN DRUG-RESISTANT PLASMODIUM-FALCIPARUM
    WILSON, CM
    SERRANO, AE
    WASLEY, A
    BOGENSCHUTZ, MP
    SHANKAR, AH
    WIRTH, DF
    [J]. SCIENCE, 1989, 244 (4909) : 1184 - 1186