SLC28A1 Membrane Protein Introduction

Introduction of SLC28A1

SLC28A1 is encoded by CNT1 or SLC28A1 gene and is also known as Sodium/nucleoside cotransporter 1, Concentrative nucleoside transporter 1 (CNT1, hCNT1), Na(+)/nucleoside cotransporter 1, Sodium-coupled nucleoside transporter 1 and Solute carrier family 28 member 1 (SLC28A1). It belongs to the SLC28 family, which is crucial determinants of response to a variety of anticancer and antiviral nucleoside analogs, as they modulate the entry of these analogs into target tissues. It is one of the three subtypes of sodium-dependent, concentrative nucleoside transporters, CNT1, CNT2, and CNT3 (SLC28A1, SLC28A2, and SLC28A3, respectively).

Function of SLC28A1 Membrane Protein

SLC28A1 transports naturally occurring pyrimidine nucleosides as well as the naturally occurring purine nucleoside, adenosine. Although SLC28A1 is pyrimidine selective, it also transports adenosine in a high-affinity, low capacity manner. Antiviral nucleoside analogs include zidovudine (3’-azido-3’-deoxythymidine, AZT), lamivudine (2’,3’-dideoxy-3’-thiacytidine, 3TC), and zalcitabine (2’,3’-dideoxycytidine,ddC) have been shown to be substrates of human SLC28A1. The cytotoxic cytidine analogs cytarabine [1-(β -d-arabinofuranosyl) cytosine, AraC] and gemcitabine (2’,2’-difluorodeoxycytidine, dFdC), used in the treatment of a wide spectrum of tumors, are substrates of human SLC28A1. Moreover, SLC28A1 is up-regulated in murine bone marrow macrophages after either LPS or TNF-α treatment, suggesting that SLC28A1 is also involved in the bone marrow macrophages development. On the other hand, according to recent reports indicate the restrictive, cell cycle-dependent expression and degradation characteristics of SLC28A1 act as limiting factors for a sustained and concentrative uptake of gemcitabine in drug-resistant pancreatic cancer, suggesting SLC28A1 as a putative tumor suppressor in pancreatic cancer.

Fig.1 The crystal structure of SLC28A1 from Vibrio cholerae (Johnson, 2014).

Application of SLC28A1 Membrane Protein in Literature

1. Gray J.H., et al. The concentrative nucleoside transporter family, SLC28. Pflügers Archiv. 2004, 447(5):728-734. PubMed ID: 2856181
   
   

   This article reports that the SLC28 family consists of three subtypes, SLC28A1, CNT2, and CNT3. The three subtypes differ in their substrate specificities and expression location, SLC28A1 is pyrimidine-nucleoside preferring, SLC28A1 is localized primarily in epithelia. Further, SLC28A1 is involved in the absorption and disposition of many nucleoside analogs.

2. Aymerich I., et al. The concentrative nucleoside transporter family (SLC28): new roles beyond salvage? Biochem. Soc. Trans. 2005, 33(1):216. PubMed ID: 15667311
   
   

   This article reveals that the up-regulation of SLC28A1 in murine bone marrow macrophages after either LPS or TNF-α treatment is consistent with CNTs playing a compensatory role in purinergic signaling by down-regulating the adenosine receptor activation that is known to impair LPS-induced production of TNF-α and nitric oxide in macrophage cell lines.

3. Bhutia Y.D., et al. CNT1 expression influences proliferation and chemosensitivity in drug-resistant pancreatic cancer cells. Cancer Res. 2011, 71(5):1825-1835. PubMed ID: 21343396
   
   

   This article indicates that SLC28A1 is involved in cellular transport, proliferation, and differentiation could synergistically impact tumor growth control in drug-resistant pancreatic cancer because SLC28A1 brings growth control by inducing differentiation (or reverting dedifferentiation) in pancreatic tumor cells.

4. Veyhl-Wichmann M., et al. Phosphorylation of RS1 (RSC1A1) Steers Inhibition of Different Exocytotic Pathways for Glucose Transporter SGLT1 and Nucleoside Transporter CNT1, and an RS1-Derived Peptide Inhibits Glucose Absorption. Mol. Pharmacol. 2016, 89(1):118. PubMed ID: 26464324
   
   

   This article describes an NH₂^- terminal domain of regulatory protein RS1 (RS1-Reg) that controls differential post-translational downregulation of SGLT1 and SLC28A1 in the plasma membrane, and SLC28A1 is involved in the exocytotic pathways of hSGLT1 and SLC28A1.

5. Gloeckner-Hofmann K., et al. Expression of the High-Affinity Fluoropyrimidine-Preferring Nucleoside Transporter hCNT1 Correlates with Decreased Disease-Free Survival in Breast Cancer. Oncology. 2006, 70(3):238-244. PubMed ID: 16837820
   
   

   The results of this article indicate that the expression of the high-affinity concentrative nucleoside transporter SLC28A1 has a prognostic value in determining disease-free survival and risk of relapse in breast cancer patients undergoing surgery followed by cyclophosphamide-methotrexate-5-fluorouracil chemotherapy.

SLC28A1 Preparation Options

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Reference

1. Johnson Z L., et al. (2014) Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters. eLife. 3:e03604.

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