A T3587G germ-line mutation of the MDR1 gene encodes a nonfunctional P-glycoprotein

Molecular Cancer Therapeutics
Kazuyoshi MutohYoshikazu Sugimoto

Abstract

The human multidrug resistance gene 1 (MDR1) encodes a plasma membrane P-glycoprotein (P-gp) that functions as an efflux pump for various structurally unrelated anticancer agents. We have identified two nonsynonymous germ-line mutations of the MDR1 gene, C3583T MDR1 and T3587G MDR1, in peripheral blood cell samples from Japanese cancer patients. Two patients carried the C3583T MDR1 allele that encodes H1195Y P-gp, whereas a further two carried T3587G MDR1 that encodes I1196S P-gp. Murine NIH3T3 cells were transfected with pCAL-MDR-IRES-ZEO constructs carrying either wild-type (WT), C3583T, or T3587G MDR1 cDNA and selected with zeocin. The resulting zeocin-resistant mixed populations of transfected cells were designated as 3T3/WT, 3T3/H1195Y, and 3T3/I1196S, respectively. The cell surface expression of I1196S P-gp in 3T3/I1196S cells could not be detected by fluorescence-activated cell sorting, although low expression of I1196S P-gp was found by Western blotting. H1195Y P-gp expression levels in 3T3/H1195Y cells were slightly lower than the corresponding WT P-gp levels in 3T3/WT cells. By immunoblotting analysis, both WT P-gp and H1195Y P-gp were detectable as a 145-kDa protein, whereas I1196S P-gp was visualized as a 140-kDa pr...Continue Reading

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Citations

Mar 14, 2007·Archives of Toxicology·Neil Macdonald, Alex Gledhill
Mar 11, 2010·Pharmacogenetics and Genomics·Laura M HodgesRuss B Altman
Feb 24, 2012·Journal of Cancer Research and Clinical Oncology·Jun WangJianshi Di
May 14, 2011·Journal of Pharmaceutical Sciences·Hiroshi NakagawaToshihisa Ishikawa
Dec 17, 2015·BMC Pharmacology & Toxicology·Shingo KondoYoshikazu Sugimoto
Feb 7, 2012·Biochemical and Biophysical Research Communications·Takaaki KawanobeYoshikazu Sugimoto

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