Different signaling pathways utilized by insulin to regulate the expression of ENT2, CNT1, CNT2 nucleoside transporters in rat cardiac fibroblasts

Podgórska, Marzena; Kocbuch, Katarzyna; Grdeń, Marzena; Szulc, Aneta; Szutowicz, Andrzej; Pawełczyk, Tadeusz

doi:10.1016/j.abb.2007.04.025

Cited by 11 publications

(8 citation statements)

References 26 publications

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“…ENT isoforms 1-4 are expressed in cardiomyocytes (10,62), with ENT1 appearing to be the predominant transporter responsible for nucleoside flux (including in cell culture models) (16,17,18,60). In rat cardiac fibroblasts, ENT1, ENT2, CNT1, and CNT2 were found to be present, and expression of ENT2, CNT1, and CNT2 was influenced by insulin (suppressing CNT1 and CNT2 but increasing ENT2 expression) (79). These data correlate with insulin-dependent changes in NT expression observed in rat lymphocytes and a reduced adenosine release by diabetic rat cardiac fibroblasts due to changes in NT expression (78,79).…”

Section: Cardiovascular Systemmentioning

confidence: 99%

Physiology of Nucleoside Transporters: Back to the Future. . . .

Rose

Coe

2008

Physiology

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Nucleoside transporters (NTs) are integral membrane proteins responsible for mediating and facilitating the flux of nucleosides and nucleobases across cellular membranes. NTs are also responsible for the uptake of nucleoside analog drugs used in the treatment of cancer and viral infections, and they are the target of certain compounds used in the treatment of some types of cardiovascular disease. The important role of NTs as drug transporters and therapeutic targets has necessarily led to intense interest into their structure and function and the relationship between these proteins and drug efficacy. In contrast, we still know relatively little about the fundamental physiology of NTs. In this review, we discuss various aspects of the physiology of NTs in mammalian systems, particularly noting tissues and cells where there has been little recent research. Our central thesis is reference back to some of the older literature, combined with current findings, will provide direction for future research into NT physiology that will lead to a fuller understanding of the role of these intriguing proteins in the everyday lives of cells, tissues, organs, and whole animals.

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Section: Cardiovascular Systemmentioning

confidence: 99%

Physiology of Nucleoside Transporters: Back to the Future. . . .

Rose

Coe

2008

Physiology

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“…Previously we have demonstrated that the expression of equilibrative nucleoside transporter 2 (ENT2), concentrative nucleoside transporter 1 (CNT1), and concentrative nucleoside transporter 2 (CNT2) in CFs is affected by insulin level, whereas the expression of equilibrative nucleoside transporter 1 (ENT1) depends on glucose level (Podgorska et al, 2006, 2007). In order to examine the effect of glucose on expression level of ENT1 in CFs the experiments were performed on cells isolated from rat heart and cultured in media containing various concentrations of glucose.…”

Section: Resultsmentioning

confidence: 99%

High glucose suppresses expression of equilibrative nucleoside transporter 1 (ENT1) in rat cardiac fibroblasts through a mechanism dependent on PKC‐ζ and MAP kinases

Grdeń

Podgórska

Kocbuch

et al. 2007

Journal Cellular Physiology

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Recently it was demonstrated that the elevated concentration of glucose but not lack of insulin is responsible for suppression of equilibrative nucleoside transporter (ENT1) in diabetic rat cardiac fibroblasts (CFs). The present study was undertaken to determine the signaling pathway utilized by glucose to regulate the expression of ENT1 in the primary culture of rat CFs. Pretreatment of CFs with Go 6983, an isozyme non-selective PKC inhibitor, prevented the high glucose (25 mM) effect on ENT1 mRNA level and nitrobenzylthioinosine (NBTI)-sensitive adenosine uptake. Similar effect was observed with a cell-permeable PKC-zeta pseudosubstrate, whereas Go 6976 a selective inhibitor of Ca(2+)-dependent PKC-alpha and PKC-beta isozymes had little effect on high glucose-induced suppression of ENT1 mRNA level. Incubation of CFs with nitric oxide (NO) donors (SNAPE, SNP) or NO synthase inhibitors (L-NAME, L-NMMA) prior to exposition of CFs to high glucose did not change the glucose effect on ENT1 mRNA level. The high glucose-induced suppression of ENT1 expression was blocked by PD9859 (an inhibitor of MEK), whereas neither wortmannin (an inhibitor of PI3K) nor rapamycin (an inhibitor of mTOR) affected the glucose action on ENT1 transcript level. Highly effective in preventing the high glucose effect on ENT1 mRNA level were GW 5074 (an inhibitor of Raf kinase) and SB 203580 (selective p38 MAPK inhibitor). These findings indicate that high glucose suppresses the expression of ENT1 in CFs by NO independent manner involving the signaling through PKC-zeta, Raf-1, MEK, and p38 MAPK pathways.

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“…9, 10, 11, 12 Reduced or even apparent loss of hCNT1 expression has been reported in a variety of human tumors, including breast, pancreatic and gynecological cancers. 6, 7, 8, 20 Furthermore, in hepatocellular carcinoma, despite highly variable expression, hCNT1 shows a trend towards reduced levels, 21, 22 whereas in hepatoblastoma and cholangiocarcinoma, hCNT1 mRNA levels are dramatically reduced compared with healthy liver.…”

Section: Discussionmentioning

confidence: 99%

“…1, 2, 3 CNT proteins, and hCNT1 in particular, are broadly detected in epithelia, although their expression is often low to negligible in undifferentiated states, as reported for intestinal crypt cells, fetal hepatocytes and human tumors. 4, 5, 6, 7, 8 hCNT1 shows complex regulation by insulin in cardiac fibroblasts 9 and by hepatocyte nuclear factor (HNF)-4, bile acids, 10 tumor necrosis factor (TNF)- α and interleukin (IL)-6 11 in hepatocytes; its expression also appears to be cell cycle dependent, showing upregulation at the S phase. 12 Most tumor-derived cell lines show low or even undetectable hCNT1 expression, although their normal counterparts normally express this membrane protein.…”

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confidence: 99%

Concentrative nucleoside transporter 1 (hCNT1) promotes phenotypic changes relevant to tumor biology in a translocation-independent manner

et al. 2013

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Nucleoside transporters (NTs) mediate the uptake of nucleosides and nucleobases across the plasma membrane, mostly for salvage purposes. The canonical NTs belong to two gene families, SLC29 and SLC28. The former encode equilibrative nucleoside transporter proteins (ENTs), which mediate the facilitative diffusion of natural nucleosides with broad selectivity, whereas the latter encode concentrative nucleoside transporters (CNTs), which are sodium-coupled and show high affinity for substrates with variable selectivity. These proteins are expressed in most cell types, exhibiting apparent functional redundancy. This might indicate that CNTs have specific roles in the physiology of the cell beyond nucleoside salvage. Here, we addressed this possibility using adenoviral vectors to restore tumor cell expression of hCNT1 or a polymorphic variant (hCNT1S546P) lacking nucleoside translocation ability. We found that hCNT1 restoration in pancreatic cancer cells significantly altered cell-cycle progression and phosphorylation status of key signal-transducing kinases, promoted poly-(ADP-ribose) polymerase hyperactivation and cell death and reduced cell migration. Importantly, the translocation-defective transporter triggered these same effects on cell physiology. Moreover, this study also shows that restoration of hCNT1 expression is able to reduce tumor growth in a mouse model of pancreatic adenocarcinoma. These data predict a novel role for a NT protein, hCNT1, which appears to be independent of its role as mediator of nucleoside uptake by cells. Thereby, hCNT1 fits the profile of a transceptor in a substrate translocation-independent manner and is likely to be relevant to tumor biology.

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Different signaling pathways utilized by insulin to regulate the expression of ENT2, CNT1, CNT2 nucleoside transporters in rat cardiac fibroblasts

Cited by 11 publications

References 26 publications

Physiology of Nucleoside Transporters: Back to the Future. . . .

Physiology of Nucleoside Transporters: Back to the Future. . . .

High glucose suppresses expression of equilibrative nucleoside transporter 1 (ENT1) in rat cardiac fibroblasts through a mechanism dependent on PKC‐ζ and MAP kinases

Concentrative nucleoside transporter 1 (hCNT1) promotes phenotypic changes relevant to tumor biology in a translocation-independent manner

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