Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation.
Recent studies have demonstrated that depletion of amino acids results in the induction of several genes and that a genomic cis-element termed amino acid response element (AARE) is required for the induction. System x(c)(-) is an anionic amino acid transport system highly specific for cystine and glutamate, and its activity is known to be induced by cystine deprivation. This transporter is composed of two protein components, xCT and 4F2 heavy chain, and xCT is thought to mediate the transport activity. In the present study, the molecular mechanism for the induction of xCT by amino acid deprivation has been investigated. In mouse NIH3T3 cells, the activity of system x(c)(-) and xCT mRNA is induced not only by deprivation of cystine but also by deprivation of other amino acids. Two AAREs, each located in the opposite direction with an intervening sequence, were found in the 5'-flanking region of the mouse xCT gene. Promoter analysis revealed that both AAREs were necessary for the maximal induction of xCT mRNA in response to the amino acid deprivation. Glucose deprivation had no effect on the induction of the activity of system x(c)(-). Electrophoretic mobility shift assay showed that ATF4, but not ATF2, is involved in the amino acid control of xCT expression. These results demonstrate that xCT is a new member of the proteins whose transcriptional control by the amino acid deprivation is mediated by AARE.
Sato
Hideyo
H
Department of Biochemistry, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Nomura
Shinobu
S
Maebara
Kanako
K
Sato
Kanako
K
Tamba
Michiko
M
Bannai
Shiro
S
D051701:Activating Transcription Factor 4; D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000502:physiology; D003553:Cystine / Q000378:metabolism*; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D016415:Sequence Alignment; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic
D027182:Amino Acid Transport System y+; D000596:Amino Acids; C081452:Atf4 protein, mouse; D027282:Fusion Regulatory Protein 1, Heavy Chain; D011993:Recombinant Fusion Proteins; C492255:Slc7a11 protein, mouse; D015534:Trans-Activators; D051701:Activating Transcription Factor 4; D018698:Glutamic Acid; D003553:Cystine