Project description:The ubiquitous efflux transporter ATP-binding cassette sub-family C member 5 (ABCC5) is present at high levels in the blood-brain barrier, neurons and glia, but its function is not known. Untargeted metabolomic screens revealed that Abcc5-/- mice accumulate endogenous glutamate conjugates in several tissues, but brain in particular. The abundant neurotransmitter N-acetylaspartylglutamate (NAAG), for example, was over 2-fold higher in Abcc5-/- brain. In line with ABCC5-mediated transport, the metabolites that accumulated in Abcc5-/- tissues were depleted in cultured cells that overexpressed human ABCC5. Using membrane vesicles, we show that ABCC5 not only transports the metabolites detected in our screen, but also a wide range of peptides containing a C-terminal glutamate. Glutamate conjugates are of physiological relevance because they can affect the function of glutamate, the principal excitatory neurotransmitter in the brain. Interestingly, we found that ABCC5 also transports exogenous glutamate analogs, like the classic excitotoxic neurotoxins kainic acid, domoic acid and N-methyl-D-aspartate (NMDA), and the therapeutic glutamate analog ZJ43. Taken together, we have identified ABCC5 as a general glutamate conjugate and analog transporter that can affect the disposition of endogenous metabolites, toxins and drugs.
Project description:Circulating Tumour Cells (CTCs) act as tumour seeds for haematogeneous melanoma spread of melanoma. Since CTCs have been reported to be heterogeneous in melanoma, the characterisation of the different melanoma CTC subpopulations harbours biological and clinical significance. For detection of melanoma CTCs, melanoma-associated markers (i.e. MCSP, melanoma-associated chondroitin sulphate proteoglycan) have been used; however, recent studies have found that melanoma CTCs commonly express ABCB5 (ATP-binding cassette sub-family B member 5) a melanoma-initiating marker. Here, we used a genome-wide expression microarray to interrogate the transcriptome of MCSP-enriched and ABCB5-enriched CTC fraction in order to provide a better understanding of their biology and role in melanoma metastasis. Findings from this study highlited the distinct transcriptional programming of both CTC subpopulations.
Project description:Pseudomonas aeruginosa is an important human pathogen which uses the type III secretion system 21 (T3SS) as a primary virulence factor to establish infections in humans. The results presented in this 22 report revealed that the ATP-binding protein PA4595 (named ArtR, a Regulator that is an ATP-activated 23 Repressor of T3SS) represses T3SS expression in P. aeruginosa. The expression of T3SS genes, 24 including exoS, exoY, exoT, exsCEBA and exsD-pscB-L, increased significantly when artR was 25 knockout. The effect of ArtR on ExsA is at the transcriptional level, not at the translational level. The 26 regulatory role and cytoplasm localization of ArtR suggest it belongs to the REG sub-family of 27 ATP-binding cassette (ABC) family. Purified GST-tagged ArtR showed ATPase activity in vitro. The 28 conserved aspartate residues in the dual Walker B motifs prove to be essential for the regulatory 29 function of ArtR. The regulation of T3SS by ArtR is unique, which does not involve the known 30 GacS/A-RsmY/Z-RsmA-ExsA pathway or Vfr. This is the first REG subfamily of ATP-binding 31 cassette that is reported to regulate T3SS genes in bacteria. The results specify a novel player in the 32 regulatory networks of T3SS in P. aeruginosa.
Project description:Irinotecan (CPT-11) is now widely used as the first-line chemotherapy for mCRC. There were 4 key enzymes for CPT-11 metabolizing, CYP3A4, UDP-glucuronosyltransferase, carboxylesterase(CES), and ATP-binding cassette (ABC) transporters. Genetic variations of those enzymes may cause the heterogeneity in safety and efficacy of CPT-11. The aim of this study is to figure out the correlation between the genetic polymorphism and the drug response.
Project description:ATP binding cassette subfamily member 1 (ABCA1) and G1 (ABCG1) are cholesterol efflux transporter to prevent excess intracellular cholesterol accumulation. We here report the deletion of Abca1 and Abcg1 results in the significant increased expression of Cd38, a multi-faceted ectoenzyme with NADase activity.
Project description:We have identified that ATP binding Cassette Subfamily G Member 2 (Abcg2) lables vascular endothelial stem cells (VESC) that can for endothelial cell (EC) colonies in vitro and functional vessels in vivo. Here we compared the transcriptome between Abcg2-expressing VESC and Abcg2- mature EC from multiple murine tissues.