Sterol transport by the human breast cancer resistance protein (ABCG2) expressed in Lactococcus lactis

被引:138
作者
Janvilisri, T [1 ]
Venter, H [1 ]
Shahi, S [1 ]
Reuter, G [1 ]
Balakrishnan, L [1 ]
van Veen, HW [1 ]
机构
[1] Univ Cambridge, Dept Pharmacol, Cambridge CB2 1PD, England
关键词
D O I
10.1074/jbc.M301358200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The human breast cancer resistance protein (BCRP, also know as ABCG2, MXR, or ABCP) is one of the more recently discovered ATP-binding cassette (ABC) transporters that confer resistance on cancer cells by mediating multidrug efflux. In the present study, we have obtained functional expression of human BCRP in the Gram-positive bacterium Lactococcus lactis. BCRP expression conferred multidrug resistance on the lactococcal cells, which was based on ATP-dependent drug extrusion. BCRP-mediated ATPase and drug transport activities were inhibited by the BCRP-specific modulator fumitremorgin C. To our knowledge these data represent the first example of the functional expression of a mammalian ABC half-transporter in bacteria. Although members of the ABCG subfamily (such as ABCG1 and ABCG5/8) have been implicated in the transport of sterols, such a role has not yet been established for BCRP. Interestingly, the BCRP-associated ATPase activity in L. lactis was significantly stimulated by (i) sterols including cholesterol and estradiol, (ii) natural steroids such as progesterone and testosterone, and (iii) the antiestrogen anticancer drug tamoxifen. In addition, BCRP mediated the efflux of [H-3] estradiol from lactococcal cells. Our findings suggest that BCRP may play a role in the transport of sterols in human, in addition to its ability to transport multiple drugs and toxins.
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页码:20645 / 20651
页数:7
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