Disease relevance of Slc28a1

• Since such drugs are to some extent cell-cycle-dependent in their cytotoxic action, we examined the relationship between CNT1 expression and cell-cycle progression in the rat hepatoma cell line FAO [1].

High impact information on Slc28a1

• BACKGROUND & AIMS: Concentrative nucleoside transporters CNT1 (pyrimidine preferring) and CNT2 (purine preferring) may be involved in the uptake of nucleoside-derived drugs used in antiviral and chemical therapies [2].
• CNT1 was sensitive to nutrient availability in small intestine and, accordingly, jejunal brush border membrane vesicles from 48-hour-fasted rats showed increased expression of CNT1 and enhanced Na(+)-dependent thymidine and gemcitabine uptake [2].
• CONCLUSIONS: Substrate availability modulates nucleoside transporter expression (CNT1) in rat jejunum in vivo [2].
• METHODS: CNT1 and CNT2 tissue distribution was determined by Western blot analysis [2].
• CNT1 was also absent in a cell line, L25, derived from the Alb-SV40 transgenic rat liver tumors, whereas another cell line, L37, derived from the normal-appearing parenchyma, retained the expression of both carrier isoforms [3].

Biological context of Slc28a1

• These data indicate that CNT1 adapts to cell-cycle progression and responds to nucleos(t)ide metabolism status, a feature that might contribute to the cytotoxic action of cell-cycle-dependent anticancer drugs [1].
• Moreover, although CNT2 expression was highly dependent on the growth characteristics of the 2 cell lines, as was CNT1 (albeit to a lower extent) in L37 cells, it was not expressed in L25 cells at any stage of cell growth [3].
• DNA sequence analysis indicated the rat BBB A-11 adenosine cDNA was identical to rat concentrative nucleoside transporter type 2 (CNT2) [4].
• Consistent with substrate specificity, results of reverse transcription-polymerase chain reaction revealed mRNA for concentrative nucleoside transporter (CNT2), which is a purine nucleoside-selective Na+/nucleoside cotransporter in the epididymis, but not for CNT1 [5].
• Preliminary studies suggested that glycosylation affects surface expression of SPNT but not CNT1 [6].

Anatomical context of Slc28a1

• METHODS: Hepatocytes isolated from fetuses, neonates and adult rats were used for uridine uptake measurements and concentrative nucleoside transporter (CNT) expression [7].
• CNT1 was also detected, albeit in small amounts, in the early/sorting endosomes [8].
• It is suggested that the Na+/nucleoside cotransporter (i.e., CNT2) may be one of the elements involved in Na+ and fluid reabsorption in the epididymis, thereby providing an optimal microenvironment for the maturation and storage of spermatozoa [5].
• Reverse transcription-polymerase chain reaction identified the mRNAs for ENT1, ENT2, and CNT2, but not CNT1 and CNT3, in neurons and astrocytes [9].
• METHODS: Rat hepatoma cell lines and hepatocytes isolated from fetuses and adult rats were used to identify single agents able to up-regulate CNT1 expression and activity in liver [10].

Associations of Slc28a1 with chemical compounds

• Low Na+-dependent uridine uptake was associated with low amounts of CNT1 and CNT2 transporter proteins, both with apparent Km values in the low micromolar range [7].
• Expression of concentrative nucleoside transporters SLC28 (CNT1, CNT2, and CNT3) along the rat nephron: effect of diabetes [11].
• When cells were synchronized using hydroxyurea (HU), which directly interacts with nucleotide metabolism by inhibiting ribonucleotide reductase, CNT1 protein amounts increased in synchronized cells and remained high during cell-cycle progression [1].
• Functional characterization of a recombinant sodium-dependent nucleoside transporter with selectivity for pyrimidine nucleosides (cNT1rat) by transient expression in cultured mammalian cells [12].
• Thus the stimulatory effect of NBTI on the concentrative nucleoside transporter of liver parenchymal cells cannot be explained by inhibition of nucleoside efflux [13].

Other interactions of Slc28a1

• BACKGROUND: The renal reabsorption of natural nucleosides and a variety of nucleoside-derived drugs relies on the function of the apically located, Na(+)-dependent, concentrative nucleoside transporters CNT1, CNT2, and CNT3 (SLC28A1, SLC28A2, and SLC28A3) [11].
• The Na+-dependent nucleoside transporter CNT1 has been identified in a caveolin-enriched plasma membrane fraction (CEF), in transcytotic endosomes, and in canalicular membranes isolated from quiescent rat liver in which the transporter appears to be biologically active [8].
• Cnt1 transcripts were highest in small intestine, followed by kidney and testes, with similar expression in both species [14].
• It is concluded that the recently characterized hepatic concentrative nucleoside transporter is under short-term hormonal regulation by glucagon, through mechanisms which involve membrane hyperpolarization, and under long-term control by insulin [15].

Analytical, diagnostic and therapeutic context of Slc28a1

• Immunocytochemistry revealed that the CNT1 protein was indeed absent in the tumor lesions [3].
• The cellular expression of equilibrative (ENT1, ENT2, ENT3) and concentrative (CNT1, CNT2, CNT3) NT subtypes was also determined using both qualitative and quantitative polymerase chain reaction techniques [16].
• The production of recombinant cNT1rat was examined by immunoblotting using an epitope-tagged construct and by analysis of inward fluxes of 3H-labelled nucleosides [12].
• Though CNT1 protein amounts increase in rat liver soon after partial hepatectomy, the physiological regulators of CNT1 expression have not yet been identified [10].

References