A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Science (Impact Factor: 33.61). 02/2007; 315(5811):525-8. DOI: 10.1126/science.1135308
Source: PubMed

ABSTRACT Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. We report that a synonymous SNP in the Multidrug Resistance 1 (MDR1) gene, part of a haplotype previously linked to altered function of the MDR1 gene product P-glycoprotein (P-gp), nonetheless results in P-gp with altered drug and inhibitor interactions. Similar mRNA and protein levels, but altered conformations, were found for wild-type and polymorphic P-gp. We hypothesize that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.

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    • "To confirm reproducibility, genotyping was repeated for 10% of the samples yielding 100% identity. ABCB1/rs1045652 [45] [46] [47] [48], ABCB1/rs1128503 [49], ABCG2/rs2231142 [50] [51] [52], ABCG2/rs2231137 [53],ABCG2/rs2622604 [53], ABCC2/rs2273697[54], ABCC2/17222723 [55] and ABCC2/rs717620 [54] were all selected based on their documented functionality from a literature search; and ABCG2/rs3789243 was chosen based on its association with inflammatory bowel disease [56], CRC [29] and low mRNA levels in morphologically normal intestinal tissue from patients with adenoma [24]. "
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    ABSTRACT: The ATP-binding cassette (ABC) transporter family transports various molecules across the enterocytes in the gut protecting the intestine against potentially harmful substances. Moreover, ABC transporters are involved in mucosal immune defence through interaction with cytokines. The study aimed to assess whether polymorphisms in ABCB1, ABCC2 and ABCG2 were associated with risk of colorectal cancer (CRC) and to investigate gene-environment (dietary factors, smoking and use of non-steroidal anti-inflammatory drugs) and gene-gene interactions between previously studied polymorphisms in IL1B and IL10 and ABC transporter genes in relation to CRC risk. We used a Danish prospective case-cohort study of 1010 CRC cases and 1829 randomly selected participants from the Danish Diet, Cancer and Health cohort. Incidence rate ratios were calculated based on Cox' proportional hazards model. None of the polymorphisms were associated with CRC, but ABCB1 and ABCG2 haplotypes were associated with risk of CRC. ABCB1/rs1045642 interacted with intake of cereals and fiber (p-Value for interaction (Pint) = 0.001 and 0.01, respectively). In a three-way analysis, both ABCB1/rs1045642 and ABCG2/rs2231137 in combination with IL10/rs3024505 interacted with fiber intake in relation to risk of CRC (Pint = 0.0007 and 0.009). Our results suggest that the ABC transporters P-glycoprotein/multidrug resistance 1 and BRCP, in cooperation with IL-10, are involved in the biological mechanism underlying the protective effect of fiber intake in relation to CRC. These results should be replicated in other cohorts to rule out chance findings.
    Scandinavian Journal of Gastroenterology 06/2015; 50(12):1-13. DOI:10.3109/00365521.2015.1056224 · 2.36 Impact Factor
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    • "The nonsynonymous mutation in ABCB1 G2677T can result in a distinct amino acid change (Ala > Ser), which exhibited lower substrate specificity and reduced drugstimulated ATPase activity as compared to the wild type [23]. The ABCB1 C3435T is a synonymous mutation but the variant can alter protein expression by affecting translation efficacy [24]. Since ABCB1 3435TT was first reported to be significantly associated with reduced ABCB1 expression in intestine compared to the CC homozygotes, numerous studies have investigated the association of ABCB1 genotype/haplotype with expression/function of the transporter in different tissues [25]. "
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    ABSTRACT: Genetic polymorphisms in ABC (ATP-binding cassette) transporter genes are associated with differential responses to chemotherapy in various cancers including pancreatic cancer. In this study, four SNPs in the ABCB1, ABCC1, and ABCG2 genes were investigated in normal and pancreatic cancerous specimens. The expression of the three transporters was also analyzed. The TT genotypes of G2677T and C3435T in ABCB1 gene were associated with lower risk of developing pancreatic cancer (P = 0.013, OR = 0.35 and P = 0.015, OR = 0.29, resp.). To our knowledge, this is the first report of the common polymorphisms in the ABCB1 gene affecting the genetic risk of developing pancreatic cancer. Moreover, the expression of ABCB1 in 2677TT and 3435TT carriers was lower compared to the wild-type homozygotes and heterozygotes. A cell viability assay, using standard pancreatic cancer cell lines, revealed that the ABCB1 2677TT-3455TT haplotype was more sensitive than the other haplotypes to gemcitabine. Conclusion. Polymorphisms in ABCB1 G2677T and G3435T were associated with differential susceptibility to pancreatic cancer and may predict responses to chemotherapy.
    Gastroenterology Research and Practice 10/2014; 2014(19 Supplement):414931. DOI:10.1155/2014/414931 · 1.75 Impact Factor
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    • "The reason may be the fact that the frequency of the various codons corresponding to the same amino-acid is variable, and the corresponding tRNA population may not be adapted to the replacement of a codon by another one: the synthesis of the protein may be slowed down, and its folding may be imperfect. An example can be found in the ABCB1 gene which encodes the multidrug resistance transporter, P-glycoprotein: a common SNP (rs1045642, C>T3435 [I1145I]), replaces the ATC codon by the ATT codon, also corresponding to isoleucine but much rarer in the human genome, so that the corresponding tRNA is also uncommon; thus, the translation rate is slowed down, which impacts the amount of protein synthesised and the level of resistance of cancer cells to anticancer drugs [3]. Another explanation comes from the fact that the three-dimensional structure of the mRNA may be different because of the replacement of a nucleotide by another one, which may have consequences on the rate of its translation into protein, therefore on the amount of the protein synthesised. "
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    ABSTRACT: There are an increasing number of studies devoted to the identification of associations between anticancer drug efficacy and toxicity and common polymorphisms present in the patients’ genome. However, many articles presenting the results of such studies do not bring the simple and necessary background information allowing the evaluation of the relevance of the study, its significance and its potential importance for patients’ treatment. This position paper first addresses clinical oncologists with the aim of giving them the basic knowledge on pharmacogenetics and on the potential use of gene polymorphisms as predictive biomarkers in routine and clinical research. A secondary objective is to give molecular biologists some recommendations on how to conceive protocols and how to publish their results when they develop pharmacogenetic studies appended to clinical trials or with autonomous goals.
    European Journal of Cancer 10/2014; 50(15). DOI:10.1016/j.ejca.2014.07.013 · 5.42 Impact Factor
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