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J. Biol. Chem., Vol. 277, Issue 31, 28127-28134, August 2, 2002
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From the Department of Molecular Pharmacology, St. Jude Children's
Research Hospital, Memphis, Tennessee 38105-2794
Mammalian target of rapamycin (mTOR) controls
initiation of translation through regulation of ribosomal p70S6 kinase
(S6K1) and eukaryotic translation initiation factor-4E (eIF4E) binding protein (4E-BP). mTOR is considered to be located predominantly in
cytosolic or membrane fractions and may shuttle between the cytoplasm
and nucleus. In most previous studies a single cell line,
E1A-immortalized human embryonic kidney cells (HEK293), has been used.
Here we show that in human malignant cell lines, human fibroblasts, and
murine myoblasts mTOR is predominantly nuclear. In contrast, mTOR is
largely excluded from the nucleus in HEK293 cells. Hybrids between
HEK293 and Rh30 rhabdomyosarcoma cells generated cells co-expressing
markers unique to HEK293 (E1A) and Rh30 (MyoD). mTOR distribution was
mainly nuclear with detectable levels in the cytoplasm. mTOR isolated
from Rh30 nuclei phosphorylated recombinant GST-4E-BP1
(Thr-46) in vitro and thus has kinase activity. We
next investigated the cellular distribution of mTOR substrates 4E-BP,
S6K1, and eIF4E. 4E-BP was exclusively detected in cytoplasmic fractions in all cell lines. S6K1 was localized in the cytoplasm in
colon carcinoma, HEK293 cells, and IMR90 fibroblasts. S6K1 was readily
detected in all cellular fractions derived from rhabdomyosarcoma cells.
eIF4E was detected in all fractions derived from rhabdomyosarcoma cells
but was not detectable in nuclear fractions from colon carcinoma HEK293
or IMR90 cells.
Predominant Nuclear Localization of Mammalian
Target of Rapamycin in Normal and Malignant Cells in
Culture*
,
*
This work was supported by United States Public Health
Services Grants CA77776, CA23099, and CA28765 (Cancer Center Support Grant) from NCI, National Institutes of Health; by a grant from Wyeth-Ayerst Laboratories; and by the American Lebanese Syrian Associated Charities.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.
Present address: Dept. of Pediatrics, Kyoto Prefectural University
of Medicine, Kyoto 602, Japan.
§
To whom correspondence should be addressed: Dept. of Molecular
Pharmacology, St. Jude Children's Research Hospital, Mail Stop 230, 332 N. Lauderdale St., Memphis, TN 38105-2794. Tel.: 901-495-3440; Fax:
901-521-1668; E-mail: peter.houghton@stjude.org.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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