Browsing by Author "Leisewitz, Andrea V."

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    A PPARs cross-talk concertedly commits C6 glioma cells to oligodendrocytes and induces enzymes involved in myelin synthesis
    (WILEY, 2008) Leisewitz, Andrea V.; Urrutia, Carolina R.; Martinez, Gabriela R.; Loyola, Gloria; Bronfman, Miguel
    Peroxisome proliferator activated receptors (PPARs, alpha, beta/delta, gamma) control lipid homeostasis and differentiation in various tissues and tumor cells. PPAR beta and PPAR gamma increase oligodendrocyte maturation in glial mixed populations and spinal cord oligodendrocytes, respectively, and PPAR beta is known to modulate the activity of other PPARs. To assess a possible interaction between PPARs in glial cell differentiation we used the undifferentiated C6 glioma cell line as model. These cells express all three PPARs, but only PPAR gamma shows transcriptional activity in agonist-based reporter gene assay. Agonist-activated PPAR gamma up-regulates oligodendrocyte markers, down-regulates an astrocyte marker, and increases alkyl-dihydroxyacetone phosphate synthase, enzyme involved in the synthesis of myelin-rich plasmalogens. Similar effects are induced in PPAR gamma overexpressing cells, which in addition show PPAR beta up-regulation. PPAR beta or PPAR alpha agonists show no effect. Nevertheless, PPAR beta overexpression up-regulates PPAR gamma and commits C6 cells to oligodendrocytes: effect that is abrogated by a PPAR gamma antagonist or PPAR gamma interference RNA. Moreover, PPAR beta overexpression also induces PPAR alpha and its target genes, including acyl-CoA oxidase, enzyme involved in very long chain fatty acid recycling, and in the synthesis of myelin components such as docosahexaenoic acid. These results indicate for the first time, that PPARs concertedly cooperate in C6 glioma cell differentiation to oligodendrocytes. Further, they suggest that active PPAR beta might be essential for increasing oligodendrocyte distinctive markers and enzymes required for myelin synthesis in C6 glioma cells through up-regulation of PPAR gamma and PPAR alpha.
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    PPAR alpha and PPAR gamma regulate the nucleoside transporter hENT1
    (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2012) Montero, Trinidad D.; Racordon, Dusan; Bravo, Loreto; Owen, Gareth I.; Bronfman, Miguel L.; Leisewitz, Andrea V.
    Human equilibrative nucleoside transporter 1 (hENT1) is an important determinant for nucleoside analog based chemotherapy success. Preliminary data suggest hENT1 regulation by PPARs. Using A2780 cells, we investigated the role of PPARs on hENT1 expression and activity.
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    Regulation of ENT1 expression and ENT1-dependent nucleoside transport by c-Jun N-terminal kinase
    (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2011) Leisewitz, Andrea V.; Zimmerman, Eric I.; Huang, Min; Jones, Shannon Z.; Yang, Jing; Graves, Lee M.
    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. (C) 2010 Elsevier Inc. All rights reserved.