TGF-β transcriptionally activates the gene encoding the high-affinity adenosine transporter CNT2 in rat liver parenchymal cells

Valdés, Raquel; Fernández‐Veledo, Sonia; Aymerich, Ivette; Casado, F. Javier; Pastor-Anglada, M

doi:10.1007/s00018-006-6240-2

Cited by 12 publications

(7 citation statements)

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“…This observation does not prove by itself that CNT2 activation actually depletes the extracellular adenosine pool, but strongly supports the view that adenosine (and other purine nucleoside) pumping into liver parenchymal cells is activated by Ai receptors in an energy-dependent manner. CNT2 in this cell type is not a target of multifunciontal cytokines, such as TNF-u or IL-6, implicated in hepatocyte priming prior to cell cycle progression (18) but it is up-regulated, at the transcriptional level, by the proapoptotic agent TGF-~l (72). Overall, all these findings taken together strongly support a role for CNT2 far beyond salvage and nutrient absorption.…”

Section: Purinergic Regulationmentioning

confidence: 76%

Concentrative nucleoside transporters (CNTs) in epithelia: from absorption to cell signaling

et al. 2007

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Concentrative and Equilibrative Nucleoside Transporter proteins (CNT and ENT, respectively) are encoded by gene families SLC28 and SLC29. They mediate the uptake of natural nucleosides and a variety of nucleoside-derived drugs, mostly used in anticancer therapy. CNT and ENT proteins are mostly localized in the apical and basolateral sides, respectively, in (re)absorptive epithelia. This anatomic distribution determines nucleoside and nucleoside-derived vectorial flux. CNT expression (particularly CNT2) is associated with differentiation and is also nutritionally regulated in intestinal epithelia, whereas ENT protein amounts (mostly ENT1) are increased when cells are exposed to proliferative stimuli such as EGF, TGF-alpha or wounding. Although all these features suggest a role for NT proteins in nucleoside salvage and (re)absorption, recent data demonstrate that CNT2 might be under purinergic control, in a manner that is dependent on energy metabolism. A physiological link between CNT2 function and intracellular metabolism is also supported by the evidence that extracellular adenosine can activate the AMP-dependent kinase (AMPK), by a mechanism which relies upon adenosine transport and phosphorylation. Thus the complex pattern of NT isoform expression in mammalian cells can fulfill physiological roles other than salvage.

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Section: Purinergic Regulationmentioning

confidence: 76%

Concentrative nucleoside transporters (CNTs) in epithelia: from absorption to cell signaling

et al. 2007

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“…Information on the transcriptional regulation of CNT1 and CNT2 is still scarce. Hepatocyte nuclear factor 4␣ is known to modulate SLC28A1 gene expression in hepatocytes (Ferná ndez-Veledo et al, 2007;Klein et al, 2009), whereas the CNT2-encoding gene is transcriptionally activated by transforming growth factor-␤ (Valdés et al, 2006), CCAAT enhancer-binding protein ␣, hepatocyte nuclear factor 3␥ (Ferná ndez-Veledo et al, 2007), and hepatocyte nuclear factor 1␣ (Yee et al, 2009). Data from this study support a major role for RS1 in the trafficking of CNT proteins from the trans-Golgi network to the plasma membrane, without consistent proof of transcriptional modulation of the SLC28 genes.…”

Section: Discussionmentioning

confidence: 99%

Role of the Transporter Regulator Protein (RS1) in the Modulation of Concentrative Nucleoside Transporters (CNTs) in Epithelia

et al. 2012

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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 ϩ -coupled, glucose transporter sodium-dependent glucose cotransporter 1, was evaluated in this study as a candidate for coordinate regulation of membrane insertion of human CNTtype 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.

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“…A four-fold increase of adenosine transport activity and CNT2 molecular expression after treatment with dexamethasone was observed while no significant impact was noted from treatment with proliferative hormones [68] . However, a more recent paper by the same research group found that TGF-b can transcriptionally up-regulate CNT2 gene expression in rat hepatocytes [69] . Adenosine transpor t and CNT2 expression are altered during cell growth cycle and differentiation.…”

Section: Regulation Of Adenosine Transport and Cnt2 Expression In Genmentioning

confidence: 98%

Adenosine: An immune modulator of inflammatory bowel diseases

Ye¹,

Rajendran²

2009

WJG

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Inflammatory bowel disease (IBD) is a common and lifelong disabling gastrointestinal disease. Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response. Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models. High extracellular adenosine suppresses and resolves chronic inflammation in IBD models. High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis. Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation.Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells, respectively. Increased extracellular adenosine levels activate the A2a receptor, which would reduce cytokines responsible for chronic inflammation.

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TGF-β transcriptionally activates the gene encoding the high-affinity adenosine transporter CNT2 in rat liver parenchymal cells

Cited by 12 publications

References 50 publications

Concentrative nucleoside transporters (CNTs) in epithelia: from absorption to cell signaling

Concentrative nucleoside transporters (CNTs) in epithelia: from absorption to cell signaling

Role of the Transporter Regulator Protein (RS1) in the Modulation of Concentrative Nucleoside Transporters (CNTs) in Epithelia

Adenosine: An immune modulator of inflammatory bowel diseases

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