ABCMdb

PMID: 19827267

Ishikawa T, Nakagawa H
Human ABC transporter ABCG2 in cancer chemotherapy and pharmacogenomics.
J Exp Ther Oncol. 2009;8(1):5-24., [PubMed]

Sentences

No. Mutations Sentence Comment

187 ABCG2 p.Cys603Gly The C603G variant was as active as was the wild type in terms of ATP-dependent MTX transport and profiles of drug resistance to SN-38 and mitoxantrone (Mitomo et al., 2003; Wakabayashi et al., 2006a). Login to comment 190 ABCG2 p.Cys608Gly ABCG2 p.Cys592Gly Although the C592G/C608G variant formed a homodimer, it exhibited lower ATP-dependent MTX transport activity and its cellular localization was remarkably altered. Login to comment 191 ABCG2 p.Cys608Gly ABCG2 p.Cys592Gly Indeed, the C592G/C608G variant was mainly localized in intracellular compartments, and its plasma membrane localization was significantly reduced. Login to comment 192 ABCG2 p.Cys608Gly ABCG2 p.Cys592Gly Furthermore, immunoblotting of the C592G/C608G variant revealed the existence of a non-glycosylated form that was observed as an additional band with a lower molecular weight (Wakabayashi et al., 2006a; Wakabayashi et al. 2007). Login to comment 194 ABCG2 p.Cys608Gly ABCG2 p.Cys592Gly As a misfolded protein, the C592G/C608G variant appears to be removed from the endoplasmic reticulum (ER) by retrotranslocation to the cytosol and then degradation by the ubiquitin-proteasome system (Wakabayashi et al., 2007). Login to comment 206 ABCG2 p.Asn596Gln The proteasome inhibitor MG132 increased the protein expression level of human ABCG2 N596Q expressed in Flp-In-293 cells, whereas it had little effect on the protein level of ABCG2 WT (Nakagawa et al., 2009). Login to comment 214 ABCG2 p.Asn596Gln Since the protein expression level of human ABCG2 N596Q was increased by treatments with bafilomycin A1 and MG132, the variant protein appears to be degraded via both the lysosomal and ubiquitin-mediated proteasomal proteolysis pathways (Nakagawa et al., 2009). Login to comment 215 ABCG2 p.Asn596Gln It is assumed that about half of the de novo synthesized N596Q variant proteins were sorted to the plasma membrane through the Golgi apparatus and then degraded in lysosomes, while the other half underwent ER-associated degradation (ERAD), i.e., ubiquitin-mediated proteasomal proteolysis. Login to comment 219 ABCG2 p.Gln141Lys The most extensively studied among those SNPs with potential clinical relevance is 421 C>A resulting in a glutamic acid to lysine substitution (Q141K) in the ABCG2 protein. Login to comment 220 ABCG2 p.Gln141Lys The Q141K SNP has been identified with varying frequencies in different ethnic groups and was found to be the most relevant in Japanese and Chinese populations (approximately 30% in the allele frequency). Login to comment 222 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ile206Leu ABCG2 p.Asn590Tyr ABCG2 p.Gln166Glu ABCG2 p.Phe208Ser ABCG2 p.Asp620Asn ABCG2 p.Thr153Met ABCG2 p.Ser441Asn ABCG2 p.Phe489Leu ABCG2 p.Phe431Leu ABCG2 p.Arg160Gln ABCG2 p.Gly51Cys ABCG2 p.Ser248Pro ABCG2 p.Phe571Ile ABCG2 p.Gln126* ABCG2 p.Arg575* ABCG2 p.Glu334* COOH H2N N590Y V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L F489L D620N R482G R482T S441N F571I OUT IN R160Q R575stop ATP-binding site Figure 7. Continued A 005-024 pp JETO-0900616-TI (Review).indd 8/7/2009 3:59:50 19 Q141K has been associated with lower levels of protein expression and impaired transport in vitro (Imai et al., 2002; Kobayashi et al., 2005; Misuarai et al., 2004; Zamber et al., 2003; Morisaki et al., 2008; Kondo et al., 2004). Login to comment 224 ABCG2 p.Gln141Lys Furthermore, the Q141K SNP was reportedly associated with a higher incidence of diarrhea in non-small cell lung cancer patients treated with gefitinib (Cusatis et al., 2006). Login to comment 225 ABCG2 p.Gln141Lys It has been demonstrated that the reduced expression levels of the Q141K variant may be due to its ubiquitin-mediated proteasomal degradation (Furukawa et al., 2009). Login to comment 226 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Impact of non-synonymous SNPs on function and protein stability Based on our functional validation in vitro, the above-mentioned 17 non-synonymous polymorphisms as well as acquired mutants (R482G and R482T) of ABCG2 were classified into four groups (Tamura et al., 2007b) (Fig. 7B). Login to comment 227 ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn ABCG2 p.Phe489Leu ABCG2 p.Ser248Pro ABCG2 p.Gln126* ABCG2 p.Glu334* The non-synonymous SNP variants Q126stop, F208S, S248P, E334stop, S441N, and F489L were defective in the active transport of methotrexate and hematoporphyrin (Tamura et al., 2006) (Fig. 7C). Login to comment 228 ABCG2 p.Arg482Thr ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly ABCG2 p.Arg482Gly ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Phe208Ser ABCG2 p.Phe208Ser ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn ABCG2 p.Ser441Asn ABCG2 p.Phe489Leu ABCG2 p.Phe489Leu ABCG2 p.Phe489Leu ABCG2 p.Phe431Leu ABCG2 p.Phe431Leu ABCG2 p.Phe431Leu ABCG2 p.Ser248Pro ABCG2 p.Ser248Pro ABCG2 p.Ser248Pro ABCG2 p.Ser441Leu Furthermore, the F208S, S248P, F431L, S441N, and F489L variants exhibited greatly altered protein expression levels and drug resistance profiles Figure 7. Continued WT V12M Q141K F208S S248P F431L S441N F489L R482G R482T Protein expression + + + - + + - + + + MTX transport + + + - - - - +/ - - Porphyrin transport + + + - - + - +/ + + SN-38 resistance + + + - +/ + - - + + MX resistance + + + - - - - - -- - - - - - - - +/ - - - - - - - - + + Doxorubicin resistance + + Daunorubicin resistance + + ATPase activity (Prazosin) + + WTV12M Q141K F431L F489L S248P F208S S441L R482G R482T ∆1.5 ∆3 ∆3.5 ∆5 ∆4 - - - - - - -- - - B 005-024 pp JETO-0900616-TI (Review).indd 8/7/2009 3:59:51 20 Journal of Experimental Therapeutics and Oncology Vol. 8 2009 (Tamura et al., 2007b). Login to comment 229 ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn In particular, expression levels of the F208S and S441N variant proteins were markedly low (Tamura et al., 2007b). Login to comment 230 ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn We have recently shown that F208S and S441N variant proteins do not undergo Golgi apparatus-mediated glycoprocessing but are passed through the so-called "ERAD" pathway. Login to comment 231 ABCG2 p.Phe208Ser ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn ABCG2 p.Ser441Asn The immature and non-glycosylated forms of F208S and S441N were detected when Flp-In-293/ABCG2 (F208S) and Flp-In-293/ABCG2 (S441N) cells were treated with MG132 for 24 h, suggesting that those variant proteins were ubiquitinated in both pre and post N-glycosylation reactions and then readily degraded in proteasomes. Login to comment 232 ABCG2 p.Arg482Thr ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly ABCG2 p.Arg482Gly ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Val12Met ABCG2 p.Ile206Leu ABCG2 p.Ile206Leu ABCG2 p.Asn590Tyr ABCG2 p.Asn590Tyr ABCG2 p.Gln166Glu ABCG2 p.Gln166Glu ABCG2 p.Phe208Ser ABCG2 p.Phe208Ser ABCG2 p.Asp620Asn ABCG2 p.Asp620Asn ABCG2 p.Thr153Met ABCG2 p.Thr153Met ABCG2 p.Ser441Asn ABCG2 p.Ser441Asn ABCG2 p.Phe489Leu ABCG2 p.Phe489Leu ABCG2 p.Phe431Leu ABCG2 p.Phe431Leu ABCG2 p.Gly51Cys ABCG2 p.Gly51Cys ABCG2 p.Ser248Pro ABCG2 p.Ser248Pro ABCG2 p.Phe571Ile ABCG2 p.Phe571Ile ABCG2 p.Gln126* ABCG2 p.Gln126* ABCG2 p.Glu334* ABCG2 p.Glu334* It is known that, in the ER, the N-linked glycans play pivotal roles in protein fold- 0.0 0.5 1.0 1.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T Methotrexatetransport (nmol/min/mgprotein) Methotrexate 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T Methotrexatetransport (nmol/min/mgprotein) MethotrexateMethotrexate Porphyrintransport (nmol/min/mgprotein) 0.0 0.1 0.2 0.3 0.4 0.5 0.0 0.1 0.2 0.3 0.4 0.5 Porphyrin Figure 7. Login to comment 235 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly The variants R482G and R482T are acquired mutations. Login to comment 251 ABCG2 p.Gln141Lys ABCG2 p.Val12Met The new camptothecin analogues that were non-substrates for ABCG2 circumvented ABCG2-mediated drug resistance without any influence from major SNPs, i.e., V12M and Q141K (Tamura et al. 2007b). Login to comment