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Nucleoside transporter expression and activity is regulated during granulocytic differentiation of NB4 cells in response to all- trans -retinoic acid

Abstract NB4 cells express multiple nucleoside transporters (NTs), including: hENT1 ( es ), and hENT2 ( ei ), and the CNT subtype referred to as, csg ; a c oncentrative s ensitive g uanosine specific transporter. csg activity is a distinguishing feature of the NB4 cell line and its presence suggests...

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Published in:Leukemia research 2007-07, Vol.31 (7), p.955-968
Main Authors: Flanagan, Sheryl A, Meckling, Kelly A
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description Abstract NB4 cells express multiple nucleoside transporters (NTs), including: hENT1 ( es ), and hENT2 ( ei ), and the CNT subtype referred to as, csg ; a c oncentrative s ensitive g uanosine specific transporter. csg activity is a distinguishing feature of the NB4 cell line and its presence suggests a particular requirement of these cells for guanosine salvage. Proliferation and differentiation pathways determine, in part, the number of NTs in cells and tissues. In this study, all- trans -retinoic acid (ATRA)-induced granulocytic differentiation of NB4 cells resulted in biphasic changes in guanosine transport. Transient increases in csg and es activity, the result of an increase in Vmax (pmol/μl s) of both transporter systems, served as early markers of differentiation while expression of a fully differentiated phenotype was accompanied by a selective loss of csg activity and the return of es activity to that of proliferating cells. Intracellular incorporation of [3 H]-guanosine decreased as cells matured despite increased transport rates and suggested a reduced intracellular requirement of NB4-granulocytes compared to their proliferating counterparts. Whether a loss of csg activity could serve to assess clinical response to differentiation therapies is not known. Nitrobenzylthioinosine (NBMPR) binding sites within nuclear membrane (NM) preparations, suggested the presence of functional intracellular NTs. An increase in plasma membrane (PM) associated transporters coincided with the early increase in guanosine transport and a decrease in NBMPR binding to NM fractions and suggests that intracellular NTs may serve as a reserve pool for translocation to the (PM) when additional transport capacity is required. The modulation of transporters during differentiation could potentially regulate drug bioavailability and cytotoxicity and should be evaluated prior to combining differentiating agents with traditional nucleoside analogs in the treatment of APL.
doi_str_mv 10.1016/j.leukres.2006.09.010
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Nitrobenzylthioinosine (NBMPR) binding sites within nuclear membrane (NM) preparations, suggested the presence of functional intracellular NTs. An increase in plasma membrane (PM) associated transporters coincided with the early increase in guanosine transport and a decrease in NBMPR binding to NM fractions and suggests that intracellular NTs may serve as a reserve pool for translocation to the (PM) when additional transport capacity is required. 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derivatives</topic><topic>Thioinosine - metabolism</topic><topic>Tretinoin - pharmacology</topic><topic>Tumor Cells, Cultured - drug effects</topic><topic>Tumor Cells, Cultured - metabolism</topic><topic>Uridine - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Flanagan, Sheryl A</creatorcontrib><creatorcontrib>Meckling, Kelly A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Leukemia research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Flanagan, Sheryl A</au><au>Meckling, Kelly A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nucleoside transporter expression and activity is regulated during granulocytic differentiation of NB4 cells in response to all- trans -retinoic acid</atitle><jtitle>Leukemia research</jtitle><addtitle>Leuk Res</addtitle><date>2007-07-01</date><risdate>2007</risdate><volume>31</volume><issue>7</issue><spage>955</spage><epage>968</epage><pages>955-968</pages><issn>0145-2126</issn><eissn>1873-5835</eissn><abstract>Abstract NB4 cells express multiple nucleoside transporters (NTs), including: hENT1 ( es ), and hENT2 ( ei ), and the CNT subtype referred to as, csg ; a c oncentrative s ensitive g uanosine specific transporter. csg activity is a distinguishing feature of the NB4 cell line and its presence suggests a particular requirement of these cells for guanosine salvage. Proliferation and differentiation pathways determine, in part, the number of NTs in cells and tissues. In this study, all- trans -retinoic acid (ATRA)-induced granulocytic differentiation of NB4 cells resulted in biphasic changes in guanosine transport. Transient increases in csg and es activity, the result of an increase in Vmax (pmol/μl s) of both transporter systems, served as early markers of differentiation while expression of a fully differentiated phenotype was accompanied by a selective loss of csg activity and the return of es activity to that of proliferating cells. Intracellular incorporation of [3 H]-guanosine decreased as cells matured despite increased transport rates and suggested a reduced intracellular requirement of NB4-granulocytes compared to their proliferating counterparts. Whether a loss of csg activity could serve to assess clinical response to differentiation therapies is not known. Nitrobenzylthioinosine (NBMPR) binding sites within nuclear membrane (NM) preparations, suggested the presence of functional intracellular NTs. An increase in plasma membrane (PM) associated transporters coincided with the early increase in guanosine transport and a decrease in NBMPR binding to NM fractions and suggests that intracellular NTs may serve as a reserve pool for translocation to the (PM) when additional transport capacity is required. The modulation of transporters during differentiation could potentially regulate drug bioavailability and cytotoxicity and should be evaluated prior to combining differentiating agents with traditional nucleoside analogs in the treatment of APL.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>17045336</pmid><doi>10.1016/j.leukres.2006.09.010</doi><tpages>14</tpages></addata></record>
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subjects Affinity Labels - metabolism
All- trans-retinoic acid
ATRA
Biological Transport
Cell Differentiation - drug effects
Cell Membrane
csg
Granulocytes - pathology
Guanosine
Guanosine - metabolism
Hematology, Oncology and Palliative Medicine
Humans
Kinetics
Leukemia, Promyelocytic, Acute - metabolism
Leukemia, Promyelocytic, Acute - pathology
NB4
NBMPR
Neutrophils - drug effects
Neutrophils - metabolism
Nucleoside transport
Nucleoside Transport Proteins - metabolism
Subcellular Fractions
Thioinosine - analogs & derivatives
Thioinosine - metabolism
Tretinoin - pharmacology
Tumor Cells, Cultured - drug effects
Tumor Cells, Cultured - metabolism
Uridine - metabolism
title Nucleoside transporter expression and activity is regulated during granulocytic differentiation of NB4 cells in response to all- trans -retinoic acid
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