title: Regulation of ENT1 expression and ENT1-dependent nucleoside transport by c-Jun N-terminal kinase.
abstract: Equilibrative nucleoside transporters (ENTs) are facilitative transporters broadly selective for pyrimidine and purine nucleosides and are essential for the modulation of nucleoside concentration and nucleoside analog availability. Resistance to nucleoside-derived drugs strongly correlates with a deficiency of ENT1 expression in several tumor cells. Thus, it is crucial to understand the mechanisms by which this transporter is modulated. Using a mouse myeloid leukemic cell line as a model, we investigated whether stress-activated kinases regulate ENT1 expression and function. JNK activation, but not p38 MAPK results in rapid loss of mENT1 function, mRNA expression and promoter activity. c-Jun but not the mutant c-Jun Ser63/73Ala, decreased mENT1 promoter activity. Moreover cJun bound to an AP-1 site identified at -1196 of the promoter, suggesting a specific role for this transcription factor in mENT1 regulation. We propose that activation of JNK-cJun pathway negatively regulates mENT1 and suggest that this mechanism might contribute to the development of nucleoside analog-derived drug resistance.
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC 27599-7365, USA. aleisewi@med.puc.cl
authors.forename: Andrea V
authors.initials: AV
authors.lastname: Leisewitz
authors.forename: Eric I
authors.initials: EI
authors.lastname: Zimmerman
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Shannon Z
authors.initials: SZ
authors.lastname: Jones
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Lee M
authors.initials: LM
authors.lastname: Graves
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D009705:Nucleosides / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D033721:Equilibrative Nucleoside Transporter 1; D048031:JNK Mitogen-Activated Protein Kinases; D009705:Nucleosides; C498476:SLC29A1 protein, mouse; C075668:Tcf3 protein, mouse