Major SNP (Q141K) Variant of Human ABC Transporter ABCG2 Undergoes Lysosomal and Proteasomal Degradations

被引:126
作者
Furukawa, Tomoka [1 ]
Wakabayashi, Kanako [1 ,2 ]
Tamura, Ai [1 ,2 ]
Nakagawa, Hiroshi [1 ]
Morishima, Yoshihiro [3 ]
Osawa, Yoichi [3 ]
Ishikawa, Toshihisa [1 ]
机构
[1] Tokyo Inst Technol, Dept Biomol Engn, Grad Sch Biosci & Biotechnol, Midori Ku, Yokohama, Kanagawa 2268501, Japan
[2] JSPS, Chiyoda Ku, Tokyo, Japan
[3] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA
关键词
ABCG2; endoplasmic reticulum associated degradation (ERAD); proteasome; SNP; ubiquitin; CANCER RESISTANCE PROTEIN; SINGLE-NUCLEOTIDE POLYMORPHISMS; ER-ASSOCIATED DEGRADATION; N-LINKED GLYCOSYLATION; ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; MULTIDRUG-RESISTANCE; GENETIC POLYMORPHISMS; MEMBRANE LOCALIZATION; PLASMA-MEMBRANE;
D O I
10.1007/s11095-008-9752-7
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Purpose. Single nucleotide polymorphisms (SNPs) of the ATP-binding cassette (ABC) transporter ABCG2 gene have been suggested to be a significant factor in patients' responses to medication and/or the risk of diseases. We aimed to evaluate the impact of the major non-synonymous SNP Q141K on lysosomal and proteasomal degradations. Methods. ABCG2 WT and the Q141K variant were expressed in Flp-In-293 cells by using the Flp recombinase system. Their expression levels and cellular localization was measured by immunoblotting and immunofluorescence microscopy, respectively. Results. The protein level of the Q141K variant expressed in Flp-In-293 cells was about half that of ABCG2 WT, while their mRNA levels were equal. The protein expression level of the Q141K variant increased about two-fold when Flp-In-293 cells were treated with MG132. In contrast, the protein level of ABCG2 WT was little affected by the same treatment. After treatment with bafilomycin A(1), the protein levels of ABCG2 WT and Q141K increased 5- and 2- fold in Flp-In-293 cells, respectively. Conclusions. The results strongly suggest that the major non-synonymous SNP Q141K affects the stability of the ABCG2 protein in the endoplasmic reticulum and enhances its susceptibility to ubiquitin-mediated proteasomal degradation.
引用
收藏
页码:469 / 479
页数:11
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