Overexpression of LAT1/CD98 light chain is sufficient to increase system L-amino acid transport activity in mouse hepatocytes but not fibroblasts.
l-amino acid transporter-1 (LAT1) is a highly conserved gene identified as a light chain of the CD98 amino acid transporter and cellular activation marker. In our previous studies we found increased expression of LAT1 in primary human cancers. We have demonstrated also that LAT1 response to arginine availability is lost in transformed and tumorigenic cells such that expression is constitutively high. System l-amino acid transport activity correlates with changes in LAT1. To assess the functional relevance of increased LAT1 expression and the requirement for 4F2 heavy chain, we overexpressed these CD98 subunits together and separately in nontransformed hepatocytes and fibroblasts. Antigen tags in the expression constructs confirmed that expressed proteins were localized to both cytoplasmic and plasma membrane locations within the cells. Overexpression of LAT1 alone in mouse hepatocytes, but not fibroblasts, was sufficient to increase system l transport, and these cells displayed a growth advantage in conditions of limited arginine. Our results suggest that loss of regulation leading to constitutive expression of LAT1 can contribute to oncogenesis. We hypothesize that the altered LAT1 expression observed in hepatocarcinogenesis gives cells a growth or survival advantage through increased transport activity in a tumor microenvironment of limited amino acid availability.
Division of Medical Oncology, Brown University School of Medicine and Graduate Program in Pathobiology, Rhode Island Hospital, Providence, Rhode Island 02903, USA.
W A
WA
Campbell
N L
NL
Thompson
D016475:3T3 Cells; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D001120:Arginine / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle; D003907:Dexamethasone / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D027261:Fusion Regulatory Protein-1; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D051379:Mice; D021122:Protein Subunits; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D000596:Amino Acids; D015703:Antigens, CD; D002352:Carrier Proteins; D027261:Fusion Regulatory Protein-1; D008164:Luminescent Proteins; D021122:Protein Subunits; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D003907:Dexamethasone; D001120:Arginine