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Am J Physiol Cell Physiol 293: C729-C737, 2007. First published May 9, 2007; doi:10.1152/ajpcell.00018.2007
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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Polyamines upregulate the mRNA expression of cationic amino acid transporter-1 in human retinal pigment epithelial cells

Shiho Kaneko,1 Emiko Okuda-Ashitaka,2 Akira Ando,1 Kazuhiro Nishimura,3 Kazuei Igarashi,3 Masahide Maeda,4 Kyoji Furuta,4 Masaaki Suzuki,4 Miyo Matsumura,1 and Seiji Ito2

Departments of 1Ophthalmology and 2Medical Chemistry, Kansai Medical University, Osaka, Japan; 3Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan; and 4Regeneration and Advanced Medical Science, Graduate School of Medicine, Gifu University, Gifu, Japan

Submitted 16 January 2007 ; accepted in final form 4 May 2007

We previously showed that ornithine was mainly transported via cationic amino acid transporter (CAT)-1 in human retinal pigment epithelial (RPE) cell line, human telomerase RT (hTERT)-RPE, and that CAT-1 was involved in ornithine cytotoxicity in ornithine-{delta}-aminotransferase (OAT)-deficient cell produced by a OAT specific inhibitor, 5-fluoromethylornithine (5-FMO). We showed here that CAT-1 mRNA expression was increased by ornithne in OAT-deficient RPE cells, which was reversed by an inhibitor of ornithine decarboxylase (ODC), {alpha}-difluoromethylornithine (DFMO). Polyamines, especially spermine, one of the metabolites of ODC, also enhanced the expression of CAT-1 mRNA. ODC mRNA expression was also increased by ornithine and polyamines, and gene silencing of ODC by siRNA decreased ornithine transport activity and its cytotoxicity. In addition, the mRNA of nuclear protein c-myc was also increased in 5-FMO- and ornithine-treated hTERT-RPE cells, and gene silencing of c-myc prevented the induction of CAT-1 and ODC. Increases in expression of CAT-1, ODC, and c-myc, and the inhibition of these stimulated expression by DFMO were also observed in primary porcine RPE cells. These results suggest that spermine plays an important role in stimulation of mRNA expression of CAT-1, which is a crucial role in ornithine cytotoxicity in OAT-deficient hTERT-RPE cells.

ornithine transport; ornithine decarboxylase; c-myc


Address for reprint requests and other correspondence: S. Ito, Dept. of Medical Chemistry, Kansai Medical Univ., 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan (e-mail: ito{at}takii.kmu.ac.jp)






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