Dataset Information

Pharmacogenomics of human ABC transporter ABCC11 (MRP8): potential risk of breast cancer and chemotherapy failure.

ABSTRACT: Some genetic polymorphisms of human ABC transporter genes are reportedly related to the risk of certain diseases and patients' responses to medication. Human ABCC11 functions as an ATP-dependent efflux pump for amphipathic anions. One non-synonymous SNP 538G>A (Gly180Arg) has been found to greatly affect the function and stability of de novo synthesized ABCC11 (Arg180) variant protein. The SNP variant lacking N-linked glycosylation is recognized as a misfolded protein in the endoplasmic reticulum (ER) and readily undergoes proteasomal degradation. This ER-associated degradation of ABCC11 protein underlies the molecular mechanism of affecting the function of apocrine glands. On the other hand, the wild type (Gly180) of ABCC11 is associated with wet-type earwax, axillary osmidrosis, colostrum secretion from the mammary gland, and the potential susceptibility of breast cancer. Furthermore, the wild type of ABCC11 reportedly has ability to efflux cyclic nucleotides and nucleoside-based anticancer drugs. The SNP (538G>A) of the ABCC11 gene is suggested to be a clinical biomarker for prediction of chemotherapeutic efficacy. Major obstacle to the successful chemotherapy of human cancer is development of resistance, and nucleoside-based chemotherapy is often characterized by inter-individual variability. This review provides an overview about the discovery and the genetic polymorphisms in human ABCC11. Furthermore we focus on the impact of ABCC11 538G>A on the apocrine phenotype, patients' response to nucleoside-based chemotherapy, and the potential risk of breast cancer.

SUBMITTER: Toyoda Y

PROVIDER: S-EPMC3319924 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Pharmacogenomics of human ABC transporter ABCC11 (MRP8): potential risk of breast cancer and chemotherapy failure.

Toyoda Yu Y Ishikawa Toshihisa T

Anti-cancer agents in medicinal chemistry 20101001 8

Some genetic polymorphisms of human ABC transporter genes are reportedly related to the risk of certain diseases and patients' responses to medication. Human ABCC11 functions as an ATP-dependent efflux pump for amphipathic anions. One non-synonymous SNP 538G>A (Gly180Arg) has been found to greatly affect the function and stability of de novo synthesized ABCC11 (Arg180) variant protein. The SNP variant lacking N-linked glycosylation is recognized as a misfolded protein in the endoplasmic reticulu ...[more]

PMID: 21182469

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Project description:The ATP-binding cassette (ABC) transporter gene superfamily is ubiquitous among extant organisms and prominently represented in plants. ABC transporters act to transport compounds across cellular membranes and are involved in a diverse range of biological processes. Thus, the applicability to biotechnology is vast, including cancer resistance in humans, drug resistance among vertebrates, and herbicide and other xenobiotic resistance in plants. In addition, plants appear to harbor the highest diversity of ABC transporter genes compared with any other group of organisms. This study applied transcriptome analysis to survey the kingdom-wide ABC transporter diversity in plants and suggest biotechnology applications of this diversity.We utilized sequence similarity-based informatics techniques to infer the identity of ABC transporter gene candidates from 1295 phylogenetically-diverse plant transcriptomes. A total of 97,149 putative (approximately 25 % were full-length) ABC transporter gene members were identified; each RNA-Seq library (plant sample) had 88?±?30 gene members. As expected, simpler organisms, such as algae, had fewer unique members than vascular land plants. Differences were also noted in the richness of certain ABC transporter subfamilies. Land plants had more unique ABCB, ABCC, and ABCG transporter gene members on average (p?<?0.005), and green algae, red algae, and bryophytes had significantly more ABCF transporter gene members (p?<?0.005). Ferns had significantly fewer ABCA transporter gene members than all other plant groups (p?<?0.005).We present a transcriptomic overview of ABC transporter gene members across all major plant groups. An increase in the number of gene family members present in the ABCB, ABCC, and ABCD transporter subfamilies may indicate an expansion of the ABC transporter superfamily among green land plants, which include all crop species. The striking difference between the number of ABCA subfamily transporter gene members between ferns and other plant taxa is surprising and merits further investigation. Discussed is the potential exploitation of ABC transporters in plant biotechnology, with an emphasis on crops.

Project description:Plants are master regulators of rhizosphere ecology, secreting a complex mixture of compounds into the soil, collectively termed plant root exudate. Root exudate composition is highly dynamic and functional, mediating economically important interactions between plants and a wide range of soil organisms. Currently we know very little about the molecular basis of root exudate composition, which is a key hurdle to functional exploitation of root exudates for crop improvement. Root expressed transporters modulate exudate composition and could be manipulated to develop beneficial plant root exudate traits. Using Virus Induced Gene silencing (VIGS), we demonstrate that knockdown of two root-expressed ABC transporter genes in tomato cv. Moneymaker, ABC-C6 and ABC-G33, alters the composition of semi-volatile compounds in collected root exudates. Root exudate chemotaxis assays demonstrate that knockdown of each transporter gene triggers the repulsion of economically relevant Meloidogyne and Globodera spp. plant parasitic nematodes, which are attracted to control treatment root exudates. Knockdown of ABC-C6 inhibits egg hatching of Meloidogyne and Globodera spp., relative to controls. Knockdown of ABC-G33 has no impact on egg hatching of Meloidogyne spp. but has a substantial inhibitory impact on egg hatching of G. pallida. ABC-C6 knockdown has no impact on the attraction of the plant pathogen Agrobacterium tumefaciens, or the plant growth promoting Bacillus subtilis, relative to controls. Silencing ABC-G33 induces a statistically significant reduction in attraction of B. subtilis, with no impact on attraction of A. tumefaciens. By inoculating selected differentially exuded compounds into control root exudates, we demonstrate that hexadecaonic acid and pentadecane are biologically relevant parasite repellents. ABC-C6 represents a promising target for breeding or biotechnology intervention strategies as gene knockdown leads to the repulsion of economically important plant parasites and retains attraction of the beneficial rhizobacterium B. subtilis. This study exposes the link between ABC transporters, root exudate composition, and ex planta interactions with agriculturally and economically relevant rhizosphere organisms, paving the way for new approaches to rhizosphere engineering and crop protection.

Dataset Information

Pharmacogenomics of human ABC transporter ABCC11 (MRP8): potential risk of breast cancer and chemotherapy failure.

Publications

Pharmacogenomics of human ABC transporter ABCC11 (MRP8): potential risk of breast cancer and chemotherapy failure.

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