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J. Biol. Chem., Vol. 276, Issue 20, 16877-16884, May 18, 2001
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From the Division of Medical Oncology, Brown University School of
Medicine and Graduate Program in Pathobiology, Rhode Island Hospital,
Providence, Rhode Island 02903
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.
Overexpression of LAT1/CD98 Light Chain Is Sufficient to
Increase System L-Amino Acid Transport Activity in
Mouse Hepatocytes but Not Fibroblasts*
*
This work was supported by National Institutes of Health
Grant CA73611 and NIEHS National Institutes of Health Training Grant T32ESO7272.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Medical
Oncology, Rhode Island Hospital, 593 Eddy St., Providence, RI 02903. Tel.: 401-444-8860; Fax: 401-444-8141; E-mail:
Nancy_Thompson@brown.edu.
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