Early induction of Na<sup>+</sup>‐dependent uridine uptake in the regenerating rat liver

Ruiz-Montasell, Bonaventura; Martínez-Mas, Joan Vicenç; Enrich, Carlos; Casado, F. Javier; Felipe, Antônio; Pastor‐Anglada, Marçal

doi:10.1016/0014-5793(93)81741-h

Cited by 31 publications

(29 citation statements)

References 35 publications

(18 reference statements)

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“…The ultimate physiological role of this response requires further analysis, although a possible relationship between cell growth and up-regulation of concentrative nucleoside transporters has recently been shown in other cell types (19,46,47). These actions appear to be dependent on protein kinase C activation, which is consistent with previous reports based on HL-60 cells induced to differentiate (20 -22).…”

Section: Tnf-␣ Modulation and Role Of Pkc In The Regulation Of Nucleosupporting

confidence: 87%

Regulation of Nucleoside Transport by Lipopolysaccharide, Phorbol Esters, and Tumor Necrosis Factor-α in Human B-lymphocytes

Soler¹,

Felipe²,

Mata³

et al. 1998

Journal of Biological Chemistry

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Nucleoside transport systems and their regulation in human B-lymphocytes have been characterized using the cell lines Raji and Bare lymphoma syndrome-1 (BLS-1) as experimental models. These cells express at least three different nucleoside transport systems as follows: a nitrobenzylthioinosine-sensitive equilibrative transport system of the es-type, which appears to be associated with hENT1 expression, and two Na ؉ -dependent transport systems that may correspond to N1 and to the recently characterized N5-type, which is nitrobenzylthioinosine-sensitive and guanosine-preferring. B cell activators such as phorbol 12-myristate 13-acetate and lipopolysaccharide (LPS) up-regulate both concentrative transport systems but down-regulate the equilibrative es-type transporter, which correlates with lower hENT1 mRNA levels. These effects are dependent on protein kinase C activity. Phorbol 12-myristate 13-acetate and LPS also induce an increase in tumor necrosis factor-␣ (TNF-␣) mRNA levels, which suggest that this cytokine may mediate some of the effects triggered by these agents, since addition of TNF-␣ alone can increase N1 and N5 transport activities by a mechanism that also depends on protein kinase C activation. Interestingly, TNF-␣ down-regulates es activity, but this effect cannot be abolished by inhibiting protein kinase C. This study reveals differential regulation of nucleoside transport systems following activation of human B-lymphocyte cell lines by agents of physiological relevance such as TNF-␣ and LPS. Moreover, it indicates that the recently characterized N5 transport system can also be regulated following B cell activation, which may be relevant to lymphocyte physiology and to the treatment of lymphocyte malignancies.Nucleosides and some of their metabolites trigger a variety of regulatory effects in biological systems. Indeed, guanosine derivatives exert immunostimulatory responses (1) and may trigger mitogenic effects in mature B-lymphocytes and, to a lesser extent, in immature B cells (2). These actions are independent of cGMP, a second messenger in B cell activation (3). Moreover, nucleosides can mimic, both in vitro (4) and in vivo (5), a T cell-like signal for B cells that enables them to elicit antigenspecific responses to T cell-dependent antigens in the absence of T cells (6). These regulatory properties of nucleosides may be dependent on their uptake into the cell (1). Thus, the characterization of nucleoside transport systems and their regulation in these cell types may contribute to a better understanding of the role of nucleosides in lymphocyte physiology. Moreover, evidence that most antiviral and antiproliferative drugs used in lymphocyte malignancies can be substrates of these transport systems (7) provides additional stimulus in the attempt to identify the major routes for nucleoside uptake into lymphocytes and how these transport systems are regulated during B cell activation.Several nucleoside transport systems have been described in mammalian cells (8). Two of them, es and ei, are equil...

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Section: Tnf-␣ Modulation and Role Of Pkc In The Regulation Of Nucleosupporting

confidence: 87%

Regulation of Nucleoside Transport by Lipopolysaccharide, Phorbol Esters, and Tumor Necrosis Factor-α in Human B-lymphocytes

Soler¹,

Felipe²,

Mata³

et al. 1998

Journal of Biological Chemistry

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“…Indeed, the Na ϩ -dependent transport activity, which has been characterized in detail both in liver plasma membrane vesicles and in hepatocytes, [30][31][32]35,43 is significantly induced (nearly a threefold increase in V max ) in the prereplicative phase of liver growth after partial hepatectomy. 33 Moreover, pathophysiological conditions associated with liver hypertrophia, like genetic obesity, are also characterized by a selective induction of the Na ϩ -dependent transport activity for nucleoside uptake. 34 In agreement with these previous observations, in this report, it is shown that the SPNT mRNA levels increase as early as 2 hours after partial hepatectomy, just before the reported increase in the V max of the Na ϩ -dependent nucleoside transport activity.…”

Section: Discussionmentioning

confidence: 99%

“…34 In agreement with these previous observations, in this report, it is shown that the SPNT mRNA levels increase as early as 2 hours after partial hepatectomy, just before the reported increase in the V max of the Na ϩ -dependent nucleoside transport activity. 33 This effect can be reproduced in culture by synchronizing FAO cells and inducing them to proliferate by serum refeeding. Thus, when liver parenchymal cells are induced to proliferate, they selectively up-regulate this concentrative transport process, SPNT, by a mechanism that is consistent with de novo synthesis of nucleoside carriers, as also shown for other transport systems like those for neutral amino acids 44,45 and the Na,K-ATPase.…”

Section: Discussionmentioning

confidence: 99%

“…In pathophysiological models of liver hypertrophy and hyperplasia, an increase in this transport activity, which relies exclusively on a V max effect, has been reported. 33,34 This induction was shown to be stable and independent of the Na ϩ transmembrane gradient. Glucagon induces this transport activity by a short-term adenosine 3Ј:5Ј cyclic monophosphate--mediated effect that depends on a transient hyperpolarization of the plasma membrane.…”

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confidence: 88%

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Differential expression and regulation of nucleoside transport systems in rat liver parenchymal and hepatoma cells

et al. 1998

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Primary cultures of rat-liver parenchymal cells show carrier-mediated nucleoside uptake by a mechanism that mainly involves concentrative, Na ؉ -dependent transport activity. In contrast, the hepatoma cell line FAO shows high nucleoside transport activity, although it is mostly accounted for by Na ؉ -independent transport processes. This is associated with a low amount of sodium purine nucleoside transporter (SPNT) mRNA. SPNT encodes a purinepreferring transporter expressed in liver parenchymal cells. To analyze whether SPNT expression is modulated during cell proliferation, SPNT mRNA levels were determined in the early phase of liver growth after partial hepatectomy and in synchronized FAO cells that had been induced to proliferate. SPNT mRNA amounts increased as early as 2 hours after partial hepatectomy. FAO cells induced to proliferate after serum refeeding show an increase in SPNT mRNA levels, which is followed by an increase in Na ؉ -dependent nucleoside uptake and occurs before the peak of 3 H-thymidine incorporation into DNA. FAO cells also express significant equilibrative nucleoside transport activity, which may be accounted for by the expression of the nitrobenzylthioinosine (NBTI)-sensitive and -insensitive isoforms, rat equilibrative nucleoside transporter 1 (rENT1) and rENT2, respectively. Interestingly, rENT2 mRNA levels follow a similar pattern to that described for SPNT when FAO cells are induced to proliferate, whereas rENT1 appears to be constitutively expressed. Liver parenchymal cells show low and negligible mRNA levels for rENT1 and rENT2 transporters, respectively, although most of the equilibrative transport activity found in hepatocytes is NBTI-resistant. It is concluded that: 1) SPNT expression is regulated both in vivo and in vitro in a way that appears to be dependent on cell cycle progression; 2) SPNT expression may be a feature of differentiated hepatocytes; and 3) equilibrative transporters are differentially regulated, rENT2 expression being cell cycle-dependent. This is consistent with its putative role as a growth factor-induced delayed early response gene. (HEPATOLOGY 1998;28:1504-1511.)Nucleosides and nucleoside analogues have a wide range of potent physiological and pharmacological properties. Purines, essentially adenosine, play a multifactorial role in liver physiology by modulating key metabolic pathways of the hepatocyte 1-5 and influencing, among other functions, hepatic arterial pressure-flow autoregulation, 6 vasodilation, 7 and superoxide anion generation. 8

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“…The studies using monensin were performed as previously described [21] by incubating, simultaneously, the ionophore at a concentration of 20 PM and the substrate, r.-alanine, at 0.25 mM. Since dilution of the ionophore required 2% DMSO, uptake rates in its absence were measured in a DMSO-supplemented medium.…”

Section: ~Eai~-sensitive and Insensitive ~A~-dependent Lala~ine Uptakementioning

confidence: 99%

Up‐regulation of system A activity in the regenerating rat liver

et al. 1993

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System A activity for neutral amino acid transport, measured as the MeAIB‐sensitive Na+‐dependent l‐alanine uptake, is induced 6 h after partial hepatectomy in plasma membrane vesicles from rat livers. Other Na+‐dependent transporters, like system ASC (MeAIB‐insensitive Na+‐dependent l‐alanine transport) and the nucleoside carrier show similar inductions. Up‐regulation of system A is not explained by changes in the dissipation rate of the Na+ transmembrane gradient, as deduced from uptake measurements performed in the presence of monensin. To determine whether induced system A shared any similarity with the activity found in hepatoma cell lines, we analyzed the N‐ethylmaleimide (NEM) sensitivity of system A in both regenerating and control rat liver plasma membrane vesicles. NEM treatment was equally effective in inhibiting system A in both experimental groups. Thus, during the prereplicative phase of liver growth, a transport activity similar to basal system A is up‐regulated in liver parenchymal cells, by a stable mechanism that does not involve changes in the Na+ transmembrane gradient.

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Early induction of Na⁺‐dependent uridine uptake in the regenerating rat liver

Cited by 31 publications

References 35 publications

Regulation of Nucleoside Transport by Lipopolysaccharide, Phorbol Esters, and Tumor Necrosis Factor-α in Human B-lymphocytes

Regulation of Nucleoside Transport by Lipopolysaccharide, Phorbol Esters, and Tumor Necrosis Factor-α in Human B-lymphocytes

Differential expression and regulation of nucleoside transport systems in rat liver parenchymal and hepatoma cells

Up‐regulation of system A activity in the regenerating rat liver

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Early induction of Na+‐dependent uridine uptake in the regenerating rat liver

Cited by 31 publications

References 35 publications

Regulation of Nucleoside Transport by Lipopolysaccharide, Phorbol Esters, and Tumor Necrosis Factor-α in Human B-lymphocytes

Regulation of Nucleoside Transport by Lipopolysaccharide, Phorbol Esters, and Tumor Necrosis Factor-α in Human B-lymphocytes

Differential expression and regulation of nucleoside transport systems in rat liver parenchymal and hepatoma cells

Up‐regulation of system A activity in the regenerating rat liver

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Early induction of Na⁺‐dependent uridine uptake in the regenerating rat liver