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Post-transcriptional Regulation of the Arginine Transporter Cat-1 by Amino Acid Availability*

K. Aulak,Rangnath Mishra,Lingyin Zhou,S. L. Hyatt,W. D. de Jonge,W. Lamers,M. Snider,M. Hatzoglou

Published 1999 in Journal of Biological Chemistry

ABSTRACT

The regulation of the high affinity cationic amino acid transporter (Cat-1) by amino acid availability has been studied. In C6 glioma and NRK kidney cells, cat-1 mRNA levels increased 3.8–18-fold following 2 h of amino acid starvation. The transcription rate of the cat-1 gene remained unchanged during amino acid starvation, suggesting a post-transcriptional mechanism of regulation. This mechanism was investigated by expressing a cat-1 mRNA from a tetracycline-regulated promoter. The cat-1 mRNA contained 1.9 kilobase pairs (kb) of coding sequence, 4.5 kb of 3′-untranslated region, and 80 base pairs of 5′-untranslated region. The full-length (7.9 kb) mRNA increased 5-fold in amino acid-depleted cells. However, a 3.4-kb species that results from the usage of an alternative polyadenylation site was not induced, suggesting that the cat-1 mRNA was stabilized bycis-acting RNA sequences within the 3′-UTR. Transcription and protein synthesis were required for the increase in full-lengthcat-1 mRNA level. Because omission of amino acids from the cell culture medium leads to a substantial decrease in protein synthesis, the translation of the increased cat-1 mRNA was assessed in amino acid-depleted cells. Western blot analysis demonstrated that cat-1 mRNA and protein levels changed in parallel. The increase in protein level was significantly lower than the increase in mRNA level, supporting the conclusion thatcat-1 mRNA is inefficiently translated when the supply of amino acids is limited, relative to amino acid-fed cells. Finally, y+-mediated transport of arginine in amino acid-fed and -starved cells paralleled Cat-1 protein levels. We conclude that thecat-1 gene is subject to adaptive regulation by amino acid availability. Amino acid depletion initiates molecular events that lead to increased cat-1 mRNA stability. This causes an increase in Cat-1 protein, and y+ transport once amino acids become available.

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