ABCMdb

PMID: 17015488

Sarkadi B, Homolya L, Szakacs G, Varadi A
Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system.
Physiol Rev. 2006 Oct;86(4):1179-236., [PubMed]

Sentences

No. Mutations Sentence Comment

466 ABCC4 p.Ser1173Ala ABCB3 p.Glu552Ala Interestingly, MDR1/Pgp variants containing combined mutations at the "catalytic carboxylate" and the contralateral signature region (E552A/S1173A) show vanadate-independent retention of ATP, suggesting that a closed formation of the dimer interface (with an occluded ATP) can indeed occur without ATP hydrolysis (374). Login to comment 495 ABCB1 p.Gly185Val A spontaneous glycine to valine mutation in the intracellular end of the third transmembrane helix of MDR1/Pgp (G185V) was shown to confer increased colchicine resistance to cells. Login to comment 801 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Mutant variants of ABCG2 The cloning variants first characterized in drug-selected mammalian cells (R482G and R482T) caused a lot of uncertainty regarding the substrate profile of ABCG2, but became also educative regarding the substrate handling of this protein. Login to comment 802 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly ABCG2 variants containing either R482G or R482T conferred increased mitoxantrone resistance to transfected cells; moreover, they introduced anthracyclin (doxorubicin) resistance and rhodamine-123 extrusion capacity, which were not found in the case of the wild-type protein (see Fig. 10, Refs. 127, 261). Login to comment 803 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly In contrast, the R482G and R482T mutants were not able to extrude methotrexate, which is a transported substrate of the wild-type ABCG2 (56, 242, 393). Login to comment 804 ABCG2 p.Arg482Ser ABCG2 p.Arg482Met Interestingly, the same phenomenon was observed in the case of the mouse Abcg2 protein; drug selection induced a mutation exactly at the same position (R482M or R482S in the mouse Abcg2), similarly altering the substrate handling of this ortholog (5). Login to comment 810 ABCG2 p.Arg482Lys Mitoxantrone was transported by all ABCG2 variants, except by R482K. Login to comment 811 ABCG2 p.Arg482Lys ABCG2 p.Arg482Tyr Rhodamine-123 was extruded by most of the mutants, except by R482K, R482Y, and the wild-type ABCG2. Login to comment 812 ABCG2 p.Arg482Lys Interestingly, the R482K variant had relatively low activity in all assays, although this mutation (Arg to Lys) represents only a minor change without charge alteration. Login to comment 819 ABCG2 p.Arg482Gly Transported substrates and inhibitors of the wild-type and R482G ABCG2 protein. Login to comment 820 ABCG2 p.Arg482Gly The Venn diagram depicts some of the transported substrates and inhibitors (in a square) for the wild-type and the R482G mutant variant of ABCG2. Login to comment 824 ABCG2 p.Thr153Met ABCG2 p.Ala149Pro ABCG2 p.Pro269Ser ABCG2 p.Arg163Lys It is worth noting that in addition to the amino acid 482 ABCG2 mutations, several other variants, A149P, T153M, R163K, and P269S, were identified in different cell lines that were also not detected in healthy individuals (188, 247) (Fig. 11). Login to comment 827 ABCG2 p.Ala24Val ABCG2 p.Gln166Glu ABCG2 p.Phe208Ser In the first cloning of the ABCG2 cDNA from human placenta (8), several sequence alterations causing amino acid changes, including A24V, Q166E, and F208S, were recorded, compared with the database reference sequence. Login to comment 997 ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ile206Leu ABCG2 p.Asn590Tyr ABCG2 p.Asp620Asn ABCG2 p.Ser441Asn ABCG2 p.Phe489Leu ABCG2 p.Phe431Leu In healthy individuals or patients, altogether eight nonsynonymous (V12M, Q141K, I206L, F431L, S441N, F489L, N590Y, D620N), five synonymous (silent) (c. Login to comment 1002 ABCG2 p.Gln126* 1425AϾG) mutations, one nonsense (Q126X, c. Login to comment 1005 ABCG2 p.Gln126* The sequence variant Q126X, leading to premature termination of protein synthesis, was consistently observed in certain Japanese cohorts, while absent in different Caucasian and African American groups (145, 148, 185). Login to comment 1006 ABCG2 p.Gln141Lys ABCG2 p.Val12Met From these numerous reported alterations, two protein variants, V12M, and Q141K, were found in relatively high frequencies, with significant differences in allele frequencies in different areas of the world (Fig. 11). Login to comment 1007 ABCG2 p.Val12Met The V12M polymorphism affects the NH2-terminal intracellular region of the protein. Login to comment 1009 ABCG2 p.Val12Met The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90%), while only 2% in a Swedish population (18, 418), and also with a significant difference in allele frequencies in Caucasian and Japanese populations. Login to comment 1010 ABCG2 p.Gln141Lys The Q141K polymorphism leads to the replacement of the uncharged glutamine residue with a positively charged lysine within the ATP-binding domain, between the Walker A motif (amino acids 83-89) and the signature region (amino acids 186-189). Login to comment 1011 ABCG2 p.Gln141Lys The Q141K variant was also detected in all ethnic groups tested: the allele frequency ranged between 1 and 35% (the African and African-American subjects with low, while the Japanese and Chinese populations with high allele frequencies; see Refs. 45, 74, 185). Login to comment 1016 ABCG2 p.Gln141Lys ABCG2 p.Val12Met (251), by using stable mammalian expression systems, found that in PA317 or HEK-293 cells the expressed Q141K ABCG2 protein had a lower expression level than the wild-type ABCG2, or the V12M variant. Login to comment 1018 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met (251) demonstrated that both the V12M and Q141K ABCG2 could reach the plasma membrane in the HEK-293 cells, while a significant portion of Q141K remained intracellular. Login to comment 1019 ABCG2 p.Gln141Lys Other studies found a 30-40% reduction in cell surface expression of the Q141K variant, despite a similar mRNA level than the wild-type ABCG2 (145, 188). Login to comment 1020 ABCG2 p.Gln141Lys Recent investigation of 99 Japanese placenta samples revealed that individuals homozygous for the Q141K variant showed significantly lower expression levels of this transporter protein, while the heterozygous samples displayed an intermediate expression level (185). Login to comment 1023 ABCG2 p.Gln141Lys ABCG2 p.Val12Met (247) expressed ABCG2 in polarized LLC-PK1 cells, and by using confocal microscopy, the authors observed that the wild-type ABCG2 and Q141K showed mainly apical staining, while the V12M variant 1210 SARKADI, HOMOLYA, SZAKA´ CS, AND VA´ RADI Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org showed mostly intracellular localization. Login to comment 1025 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Val12Met (188) also used LLC-PK1 cells to express the V12M and Q141K variants and found that all polymorphisms, including V12M and Q141K, had an apical localization. Login to comment 1028 ABCG2 p.Gln141Lys ABCG2 p.Val12Met (247), when the V12M or Q141K-transfected LLC-PK1 cells were challenged by mitoxantrone, topotecan, or an indolocarbazole topoisomerase I inhibitor. Login to comment 1030 ABCG2 p.Gln141Lys (251) found that only the Q141K variant had a moderately lower level resistance against mitoxantrone, topotecan, or SN-38, compared with the wild-type ABCG2-transfected cells. Login to comment 1032 ABCG2 p.Gln141Lys Q141K is mapped to a functionally important ABC region of ABCG2; therefore, it is possible that the ATPase activity of this variant is altered. Login to comment 1033 ABCG2 p.Gln141Lys ABCG2 p.Val12Met Two studies compared the vanadate-sensitive ATPase activity of ABCG2 V12M and Q141K variants, using Sf9 (Spodoptera frugiperda) cell membranes (247, 251). Login to comment 1034 ABCG2 p.Gln141Lys A reduced basal ATPase activity was observed by both groups for the Q141K variant. Login to comment 1035 ABCG2 p.Val12Met On the other hand, the V12M ABCG2 showed a similar ATPase activity as the wild-type protein. Login to comment 1038 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met Clearly, more detailed studies are required to clarify the mechanism of a reduced protein expression for Q141K, and the altered cellular localization found for the V12M and Q141K variants under certain conditions. Login to comment 1047 ABCG2 p.Gln141Lys A recent investigation performed an exploratory, retrospective evaluation of the functional consequence of the ABCG2 Q141K variant in 20 adult patients, treated with diflomotecan, a synthetic derivative of camptothecin (350). Login to comment 1050 ABCG2 p.Gln141Lys This observation is in harmony with studies indicating a reduced protein expression and function for the Q141K variant, while it seems to contradict the results of De Jong et al. Login to comment 1052 ABCG2 p.Gln141Lys As mentioned above, the allele frequency of Q141K varies in diverse populations, and in Japan and China, this polymorphism appears to be common, with an overall allele frequency of ϳ30%. Login to comment 1084 ABCG2 p.Lys86Met Clearly, a nonfunctional mutant (K86M) ABCG2 variant induces a dominant negative effect, that is, a nonfunctional dimer formation suppresses the activity of the wild-type protein (93, 166). Login to comment 1113 ABCG2 p.Arg482Gly Because the substrate specificity of the R482G variant of ABCG2 differs from that of the wild-type protein, this mutant has a special advantage in gene therapy applications. Login to comment