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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
1995-2-13
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pubmed:databankReference |
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pubmed:abstractText |
The immunosuppressive drug, rapamycin, interferes with an undefined signaling pathway required for the progression of G1-phase T-cells into S phase. Genetic analyses in yeast indicate that binding of rapamycin to its intracellular receptor, FKBP12, generates a toxic complex that inhibits cell growth in G1 phase. These analyses implicated two related proteins, TOR1 and TOR2, as targets of the FKBP12-rapamycin complex in yeast. In this study, we have used a glutathione S-transferase (GST)-FKBP12-rapamycin affinity matrix to isolate putative mammalian targets of rapamycin (mTOR) from tissue extracts. In the presence of rapamycin, immobilized GST-FKBP12 specifically precipitates similar high molecular mass proteins from both rat brain and murine T-lymphoma cell extracts. Binding experiments performed with rapamycin-sensitive and -resistant mutant clones derived from the YAC-1 T-lymphoma cell line demonstrate that the GST-FKBP12-rapamycin complex recovers significantly lower amounts of the candidate mTOR from rapamycin-resistant cell lines. The latter results suggest that mTOR is a relevant target of rapamycin in these cells. Finally, we report the isolation of a full-length mTOR cDNA that encodes a direct ligand for the FKBP12-rapamycin complex. The deduced amino acid sequence of mTOR displays 42 and 45% identity to those of yeast TOR1 and TOR2, respectively. These results strongly suggest that the FKBP12-rapamycin complex interacts with homologous ligands in yeast and mammalian cells and that the loss of mTOR function is directly related to the inhibitory effect of rapamycin on G1- to S-phase progression in T-lymphocytes and other sensitive cell types.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Primers,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Fungal Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Heat-Shock Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/MTOR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphotransferases (Alcohol Group...,
http://linkedlifedata.com/resource/pubmed/chemical/Polyenes,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Saccharomyces cerevisiae Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Sirolimus,
http://linkedlifedata.com/resource/pubmed/chemical/TOR Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/TOR1 protein, S cerevisiae,
http://linkedlifedata.com/resource/pubmed/chemical/Tacrolimus Binding Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
13
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pubmed:volume |
270
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
815-22
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:7822316-Amino Acid Sequence,
pubmed-meshheading:7822316-Animals,
pubmed-meshheading:7822316-Base Sequence,
pubmed-meshheading:7822316-Carrier Proteins,
pubmed-meshheading:7822316-Cell Cycle Proteins,
pubmed-meshheading:7822316-DNA, Complementary,
pubmed-meshheading:7822316-DNA Primers,
pubmed-meshheading:7822316-DNA-Binding Proteins,
pubmed-meshheading:7822316-Fungal Proteins,
pubmed-meshheading:7822316-Heat-Shock Proteins,
pubmed-meshheading:7822316-Humans,
pubmed-meshheading:7822316-Lymphoma, T-Cell,
pubmed-meshheading:7822316-Molecular Sequence Data,
pubmed-meshheading:7822316-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:7822316-Phosphotransferases (Alcohol Group Acceptor),
pubmed-meshheading:7822316-Polyenes,
pubmed-meshheading:7822316-Protein Kinases,
pubmed-meshheading:7822316-Rats,
pubmed-meshheading:7822316-Rats, Sprague-Dawley,
pubmed-meshheading:7822316-Saccharomyces cerevisiae Proteins,
pubmed-meshheading:7822316-Sequence Homology, Amino Acid,
pubmed-meshheading:7822316-Sirolimus,
pubmed-meshheading:7822316-TOR Serine-Threonine Kinases,
pubmed-meshheading:7822316-Tacrolimus Binding Proteins,
pubmed-meshheading:7822316-Tumor Cells, Cultured
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pubmed:year |
1995
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pubmed:articleTitle |
Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells.
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pubmed:affiliation |
Department of Pharmacology, Mayo Clinic, Rochester, Minnesota 55905.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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