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Gene Review

SLC28A1  -  solute carrier family 28 (concentrative...

Homo sapiens

Synonyms: CNT 1, CNT1, Concentrative nucleoside transporter 1, HCNT1, Na(+)/nucleoside cotransporter 1, ...
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Disease relevance of SLC28A1

  • CONCLUSION: In summary, human pancreatic adenocarcinoma cells overexpress hENT1, although they retain the ability to express a functional hCNT1 transporter, an isoform that confers sensitivity to gemcitabine [1].
  • Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2',2'-difluorodeoxycytidine- induced cytotoxicity [1].
  • Both proteins belong to a gene family that includes the NupC proton/nucleoside symporter of E. coli. cDNAs encoding members of the CNT family have been isolated from rat tissues (jejunum, brain, liver; rCNT1 and rCNT2/SPNT) and, most recently, human kidney (hCNT1 and hSPNT1) [2].
  • These 2 antisera, along with a previously characterized antibody that specifically recognizes the high-affinity Na-dependent concentrative NT, hCNT1, have been used to analyze, using a tissue array approach, NT expression in gynecologic cancers (90 ovarian, 80 endometrial and 118 uterine cervix carcinomas) [3].
  • Only a few endometrial carcinomas (15%) were found to be negative for hCNT1, but they all retained hENT1 and hENT2 expression [3].

High impact information on SLC28A1

  • RESULTS: Gemcitabine was transported by most of the tested proteins (the exceptions being the purine-selective rCNT2 and hCNT2), with the greatest uptake occurring in oocytes producing recombinant rCNT1 and hCNT1 [4].
  • Influxes of gemcitabine mediated by hCNT1, hENT1, and hENT2 were saturable and conformed to Michaelis-Menten kinetics with apparent K(m) values of 24, 160, and 740 microM, respectively [4].
  • External application of gemcitabine to oocytes producing recombinant hCNT1 induced an inward current, which demonstrated that hCNT1 functions as a Na(+)/nucleoside co-transport protein and confirmed the transporter's ability to transport gemcitabine [4].
  • We also used the two-electrode, voltage-clamp technique to investigate the electrophysiology of hCNT1-mediated gemcitabine transport [4].
  • Thus, hCNT1 cannot be considered a broad-selectivity pyrimidine nucleoside carrier; in fact, very slight changes in substrate structure provoke a dramatic shift in selectivity [5].

Biological context of SLC28A1


Anatomical context of SLC28A1

  • Reverse transcription-PCR analysis of the other four cloned plasma membrane transporter mRNAs revealed very different expression patterns among NP cell lines, with apparent selective loss or decrease of hCNT mRNAs [1].
  • In HeLa cells with recombinant human concentrative nucleoside transporter (hCNT) 1 or hCNT3 and pharmacologically blocked hENT1 and hENT2, transport of 10 microM[3H]TaraC and [3H]araC was not detected [8].
  • The CNT1 and CNT2 transporters are co-expressed in liver parenchymal cells and macrophages, two suitable models in which to study cell cycle progression [7].
  • When produced in Xenopus oocytes, recombinant hCNT1 is selective for pyrimidine nucleosides (system cit), whereas hCNT2 is selective for purine nucleosides (system cif) [9].
  • In uterine cervix tumors, the loss of expression of hCNT1 was significantly associated with the adenocarcinoma subtype [3].

Associations of SLC28A1 with chemical compounds

  • The apparent affinities of recombinant transporters (produced in yeast) for a panel of cytosine-containing nucleosides yielded results that were consistent with the observed low-permeant activities of TaraC and araC for hENT1/2 and negligible permeant activities for hCNT1/2/3 [8].
  • These subtypes differ in their substrate specificities: CNT1 is pyrimidine-nucleoside preferring, CNT2 is purine-nucleoside preferring, and CNT3 transports both pyrimidine and purine nucleosides [10].
  • On its own, the S353T mutation converted hCNT1 into a transporter with novel uridine-selective transport properties [9].
  • Additional mutation of Leu(354) to Val (which had no effect on its own) increased the adenosine transport capability of hCNT1/S319G/Q320M/S353T, producing a full cif-type transporter phenotype [9].
  • Mutation of Ser(319) in TM 7 of hCNT1 to Gly enabled transport of purine nucleosides, whereas concurrent mutation of Gln(320) to Met (which had no effect on its own) augmented this transport [9].
  • Glu-322, the residue having the greatest influence on hCNT1 transport function, exhibited uridine-protected inhibition by p-chloromercuriphenyl sulfonate and 2-aminoethyl methanethiosulfonate when converted to cysteine [11].
  • Although this cysteine residue is also present in hCNT1 and hCNT2, neither transporter was affected by PCMBS [12].

Other interactions of SLC28A1

  • The introduction by gene transfer of hENT2 and hCNT1 activities, respectively, into nucleoside transport-defective CEM cells increased sensitivity to both drugs moderately and slightly [8].
  • The human concentrative nucleoside transporter, CNT3 (SLC28A3), plays an important role in mediating the cellular entry of a broad array of physiological nucleosides and synthetic anticancer nucleoside analog drugs [13].
  • Simultaneous expression of hCNT1-CFP and hENT1-YFP in Madin-Darby canine kidney cells. Localization and vectorial transport studies [14].
  • By contrast, CNT1, which is a target of multifunctional cytokines involved in liver cell proliferation, does not respond to TGF-beta1 treatment [15].
  • The percentage of hCNT1-positive cells correlated positively with the expression of thymidine phosphorylase and dihydropyrimidine dehydrogenase [16].

Analytical, diagnostic and therapeutic context of SLC28A1


  1. Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2',2'-difluorodeoxycytidine- induced cytotoxicity. García-Manteiga, J., Molina-Arcas, M., Casado, F.J., Mazo, A., Pastor-Anglada, M. Clin. Cancer Res. (2003) [Pubmed]
  2. Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Na+/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine. Ritzel, M.W., Yao, S.Y., Ng, A.M., Mackey, J.R., Cass, C.E., Young, J.D. Mol. Membr. Biol. (1998) [Pubmed]
  3. Expression of the nucleoside-derived drug transporters hCNT1, hENT1 and hENT2 in gynecologic tumors. Farré, X., Guillén-Gómez, E., Sánchez, L., Hardisson, D., Plaza, Y., Lloberas, J., Casado, F.J., Palacios, J., Pastor-Anglada, M. Int. J. Cancer (2004) [Pubmed]
  4. Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. Mackey, J.R., Yao, S.Y., Smith, K.M., Karpinski, E., Baldwin, S.A., Cass, C.E., Young, J.D. J. Natl. Cancer Inst. (1999) [Pubmed]
  5. Interaction of nucleoside inhibitors of HIV-1 reverse transcriptase with the concentrative nucleoside transporter-1 (SLC28A1). Cano-Soldado, P., Lorráyoz, I.M., Molina-Arcas, M., Casado, F.J., Martinez-Picado, J., Lostao, M.P., Pastor-Anglada, M. Antivir. Ther. (Lond.) (2004) [Pubmed]
  6. Transcription factors involved in the expression of SLC28 genes in human liver parenchymal cells. Fern??ndez-Veledo, S., Jover, R., Casado, F.J., G??mez-Lech??n, M.J., Pastor-Anglada, M. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  7. The concentrative nucleoside transporter family (SLC28): new roles beyond salvage? Aymerich, I., Duflot, S., Fernández-Veledo, S., Guillén-Gómez, E., Huber-Ruano, I., Casado, F.J., Pastor-Anglada, M. Biochem. Soc. Trans. (2005) [Pubmed]
  8. The role of human nucleoside transporters in cellular uptake of 4'-thio-beta-D-arabinofuranosylcytosine and beta-D-arabinosylcytosine. Clarke, M.L., Damaraju, V.L., Zhang, J., Mowles, D., Tackaberry, T., Lang, T., Smith, K.M., Young, J.D., Tomkinson, B., Cass, C.E. Mol. Pharmacol. (2006) [Pubmed]
  9. Identification of amino acid residues responsible for the pyrimidine and purine nucleoside specificities of human concentrative Na(+) nucleoside cotransporters hCNT1 and hCNT2. Loewen, S.K., Ng, A.M., Yao, S.Y., Cass, C.E., Baldwin, S.A., Young, J.D. J. Biol. Chem. (1999) [Pubmed]
  10. The concentrative nucleoside transporter family, SLC28. Gray, J.H., Owen, R.P., Giacomini, K.M. Pflugers Arch. (2004) [Pubmed]
  11. Conserved glutamate residues are critically involved in Na+/nucleoside cotransport by human concentrative nucleoside transporter 1 (hCNT1). Yao, S.Y., Ng, A.M., Slugoski, M.D., Smith, K.M., Mulinta, R., Karpinski, E., Cass, C.E., Baldwin, S.A., Young, J.D. J. Biol. Chem. (2007) [Pubmed]
  12. A proton-mediated conformational shift identifies a mobile pore-lining cysteine residue (Cys-561) in human concentrative nucleoside transporter 3. Slugoski, M.D., Ng, A.M., Yao, S.Y., Smith, K.M., Lin, C.C., Zhang, J., Karpinski, E., Cass, C.E., Baldwin, S.A., Young, J.D. J. Biol. Chem. (2008) [Pubmed]
  13. Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3). Badagnani, I., Chan, W., Castro, R.A., Brett, C.M., Huang, C.C., Stryke, D., Kawamoto, M., Johns, S.J., Ferrin, T.E., Carlson, E.J., Burchard, E.G., Giacomini, K.M. Pharmacogenomics J. (2005) [Pubmed]
  14. Simultaneous expression of hCNT1-CFP and hENT1-YFP in Madin-Darby canine kidney cells. Localization and vectorial transport studies. Lai, Y., Bakken, A.H., Unadkat, J.D. J. Biol. Chem. (2002) [Pubmed]
  15. TGF-beta transcriptionally activates the gene encoding the high-affinity adenosine transporter CNT2 in rat liver parenchymal cells. Vald??s, R., Fern??ndez-Veledo, S., Aymerich, I., Casado, F.J., Pastor-Anglada, M. Cell. Mol. Life Sci. (2006) [Pubmed]
  16. Expression of the high-affinity fluoropyrimidine-preferring nucleoside transporter hCNT1 correlates with decreased disease-free survival in breast cancer. Gloeckner-Hofmann, K., Guillén-Gómez, E., Schmidtgen, C., Porstmann, R., Ziegler, R., Stoss, O., Casado, F.J., Rüschoff, J., Pastor-Anglada, M. Oncology (2006) [Pubmed]
  17. The broadly selective human Na+/nucleoside cotransporter (hCNT3) exhibits novel cation-coupled nucleoside transport characteristics. Smith, K.M., Slugoski, M.D., Loewen, S.K., Ng, A.M., Yao, S.Y., Chen, X.Z., Karpinski, E., Cass, C.E., Baldwin, S.A., Young, J.D. J. Biol. Chem. (2005) [Pubmed]
  18. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Spratlin, J., Sangha, R., Glubrecht, D., Dabbagh, L., Young, J.D., Dumontet, C., Cass, C., Lai, R., Mackey, J.R. Clin. Cancer Res. (2004) [Pubmed]
  19. Molecular cloning and functional expression of cDNAs encoding a human Na+-nucleoside cotransporter (hCNT1). Ritzel, M.W., Yao, S.Y., Huang, M.Y., Elliott, J.F., Cass, C.E., Young, J.D. Am. J. Physiol. (1997) [Pubmed]
  20. The increment of purine specific sodium nucleoside cotransporter mRNA in experimental fibrotic liver induced by bile duct ligation and scission. Lee, S.H., Chae, K.S., Nan, J.X., Sohn, D.H. Arch. Pharm. Res. (2000) [Pubmed]
  21. Uridine binding motifs of human concentrative nucleoside transporters 1 and 3 produced in Saccharomyces cerevisiae. Zhang, J., Visser, F., Vickers, M.F., Lang, T., Robins, M.J., Nielsen, L.P., Nowak, I., Baldwin, S.A., Young, J.D., Cass, C.E. Mol. Pharmacol. (2003) [Pubmed]
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