Disease relevance of SLC29A1

• 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].
• Expression of human equilibrative nucleoside transporter 1 (hENT1) and its correlation with gemcitabine uptake and cytotoxicity in mantle cell lymphoma [2].
• Chronic lymphocytic leukemia (CLL) cells express both SLC28- and SLC29-related mRNA, although transport function seems to be mostly related to ENT-type transporters [2].
• Mitochondrial expression of the human equilibrative nucleoside transporter 1 (hENT1) results in enhanced mitochondrial toxicity of antiviral drugs [3].
• Human equilibrative nucleoside transporter-1 (hENT1) is required for the transcriptomic response of the nucleoside-derived drug 5'-DFUR in breast cancer MCF7 cells [4].

Psychiatry related information on SLC29A1

• Total sleep deprivation dramatically diminished the amounts of CNT2 mRNA, whereas ENT1 mRNA remained unchanged [5].

High impact information on SLC29A1

• Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia [6].
• Examination of the ENT1 promoter identified a hypoxia inducible factor 1 (HIF-1)-dependent repression of ENT1 during hypoxia [6].
• HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia [6].
• 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 [7].
• Inhibition of SLC29A1 by nitrobenzylmercaptopurine ribonucleoside (NBMPR) caused a 33% to 45% reduction of TGN in ALL cells in vitro (P < .006), consistent with the gene expression findings [8].

Chemical compound and disease context of SLC29A1

• The mitochondrial toxicity of FIAU to Madin-Darby canine kidney cells was enhanced by hENT1-YFP, even when hENT1 activity on the plasma membrane was selectively blocked by 10 nm nitrobenzylthioinosine [3].
• Thus, reduced adenosine transport may result from downregulation of SLC29A1 expression by NO in HUVEC from gestational diabetes [9].
• HUVEC from gestational diabetes exhibit reduced SLC29A1 promoter activity when transfected with pGL3-hENT1(-2154) compared with pGL3-hENT1(-1114) constructs, an effect blocked by N(G)-nitro-L-arginine methyl ester (L-NAME, NOS inhibitor), but unaltered by S-nitroso-N-acetyl-L,D-penicillamine (SNAP, NO donor) [9].
• The human and rat nucleoside transport proteins hENT1, rENT1, hENT2 and rENT2 were produced in Xenopus oocytes and investigated for their ability to transport three 3'-deoxy-nucleoside analogues, ddC (2'3'-dideoxycytidine), AZT (3'-azido-3'-deoxythymidine) and ddI (2'3'-dideoxyinosine), used in human immunodeficiency virus (HIV) therapy [10].
• Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENT1): implications for interspecies differences in mitochondrial toxicity of fialuridine [11].

Biological context of SLC29A1

• This 456-residue protein is 46% identical in amino acid sequence with hENT1 and corresponds to a full-length form of the delayed-early proliferative response gene product HNP36, a protein of unknown function previously cloned in a form bearing a sequence deletion [12].
• In this study we identified down-regulation of ENT1 as the factor responsible for Ara-C resistance, and this knowledge may be used to devise a clinical regimen that will overcome the resistance [13].
• Accordingly, Ara-C-resistant cells showed low growth rates, which were restored by transfection with ENT1 [13].
• The best-characterised members of the family, hENT1 and hENT2, possess similar broad substrate specificities for purine and pyrimidine nucleosides, but hENT2 in addition efficiently transports nucleobases [14].
• The observed modification in es activity was probably due to a CK2alpha'-mediated change in the phosphorylation state of the ENT1 protein, or an interacting protein, effecting an increase in the plasma membrane lifetime of the transport proteins [15].

Anatomical context of SLC29A1

• The first mammalian examples of the equilibrative nucleoside transporter family to be characterized, hENT1 and hENT2, were passive transporters located predominantly in the plasma membranes of human cells [16].
• RESULTS: All of the cell lines take up gemcitabine mostly via the hENT1 transporter, which is expressed at high levels [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 [17].
• Uptake studies demonstrated that the majority of adenosine transport was mediated by hENT1, which was localized to both apical and basolateral membranes, with a smaller hENT2-mediated component in basolateral membranes [18].
• In contrast, recombinant hENT1 and rENT1 mediated negligible oocyte fluxes of hypoxanthine relative to hENT2 and rENT2 [19].

Associations of SLC29A1 with chemical compounds

• 7-, and 19.3-fold lower affinity than hENT1 for thymidine, adenosine, cytidine, and guanosine, respectively [20].
• With hENT1 being more sensitive, there is a 7000-fold and 71-fold difference in sensitivity to nitrobenzylthioinosine (NBMPR) (IC(50), 0.4 +/- 0.1 nM versus 2.8 +/- 0.3 microM) and dipyridamole (IC(50), 5.0 +/- 0.9 nM versus 356 +/- 13 nM), respectively [20].
• Interestingly, mutant E206Q, which possesses the equivalent residue in ENT1, gained uridine transport activity [21].
• In contrast, the affinity of hENT2 for inosine is 4-fold higher than hENT1 [20].
• The nucleobase hypoxanthine inhibits [(3)H]uridine uptake by hENT2 but has minimal effect on hENT1 [20].

Regulatory relationships of SLC29A1

• We also observed that p53 status influenced correlations between ENT1 transporter gene RNA levels and sensitivity to the drugs tiazafurin, AZQ and 3-deazauridine [22].
• However, ADP responses were significantly enhanced in the presence of the ENT1 nucleoside transporter inhibitors dipyridamole and NBTI and were significantly inhibited by adenosine deaminase, indicating a role for extracellular adenosine [23].

Other interactions of SLC29A1

• 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 [17].
• DESIGN AND METHODS: The relative amounts of hENT1 and hENT2-related mRNA and protein were analyzed in five MCL cell lines and 20 primary MCL tumors by real-time quantitative reverse transcriptase polymerase chain reaction and western blots [2].
• This paper summarizes current knowledge of the family and reports on the identification of a novel mammalian ENT isoform, designated ENT3, from mouse and human tissues [24].
• Addition of a hydroxyl group around the 2-position of purine (or 3-position of pyrimidine) may increase inhibition to hCNT2 transporter; addition of hydroxyl group around the 2,7-position of purine (or the 3,5-position of pyrimidine) would increase the inhibition to hENT1 transporter [25].
• Instead, 2-CADO, but not adenosine, is taken up into RA-FLSs via human equilibrative nucleoside transporter-1, where it is phosphorylated by adenosine kinase [26].

Analytical, diagnostic and therapeutic context of SLC29A1

• In this study, using polyclonal monospecific antibodies we have observed a significant correlation between the expression of hENT2 by Western blot and fludarabine uptake via hENT carriers and also with ex vivo sensitivity of CLL cells to fludarabine [27].
• Molecular cloning and characterization of a nitrobenzylthioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta [12].
• Moreover, analysis by RT-PCR showed that BeWo cells express mRNA of hCNT3, hENT1 and hENT2 [28].
• Quantitative PCR showed a transient decrease in the expression of both hENT1 (human ENT1) and hENT2 mRNAs within 4-12 h of induction of the inactive CK2alpha' subunit, but both transcripts had returned to control levels by 24 h [15].
• Immunohistochemistry for hENT1 shows promise as a molecular predictive assay to appropriately select patients for palliative gemcitabine chemotherapy but requires formal validation in prospective, randomized trials [29].

References