Abstract
SLC28 genes encode three plasma membrane transporter proteins, human concentrative nucleoside transporter (CNT)1, CNT2, and CNT3, all of which are implicated in the uptake of natural nucleosides and a variety of nucleoside analogs used in the chemotherapy of cancer and viral and inflammatory diseases. Mechanisms determining their trafficking toward the plasma membrane are not well known, although this might eventually become a target for therapeutic intervention. The transporter regulator RS1, which was initially identified as a short-term, post-transcriptional regulator of the high-affinity, Na+-coupled, glucose transporter sodium-dependent glucose cotransporter 1, was evaluated in this study as a candidate for coordinate regulation of membrane insertion of human CNT-type proteins. With a combination of studies with mammalian cells, Xenopus laevis oocytes, and RS1-null mice, evidence that RS1 down-regulates the localization and activity at the plasma membrane of the three members of this protein family (CNT1, CNT2, and CNT3) is provided, which indicates the biochemical basis for coordinate regulation of nucleoside uptake ability in epithelia and probably in other RS1-expressing cell types.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the Ministerio de Ciencia e Innovación (Spain) [Grants SAF2008-0577, SAF2011-23660], Generalitat de Catalunya [Grant 2009SGR624], and Deutsche Forschungsgemeinschaft (Germany) [Grant SFB 487/C1].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- CNT
- concentrative nucleoside transporter
- hCNT
- human concentrative nucleoside transporter
- mCNT
- mouse concentrative nucleoside transporter
- ENT
- equilibrative nucleoside transporter
- hRS1
- human RS1
- ER
- endoplasmic reticulum
- BBMV
- brush border membrane vesicle
- siRNA
- short interfering RNA
- GST
- glutathione transferase
- IRIP
- ischemia/reperfusion-inducible protein
- OCT
- organic cation transporter
- PCR
- polymerase chain reaction
- SGLT1
- sodium-dependent glucose cotransporter 1.
- Received November 28, 2011.
- Accepted April 4, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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