Abstract
The structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways. FKBP12-rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma, liver and T cells as well as in yeast, and interferes with mitogenic signalling pathways that are involved in G1 progression, namely with activation of the protein p70S6k (refs 5, 11-13) and cyclin-dependent kinases. Here we isolate a mammalian FKBP-rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly, these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Carrier Proteins / analysis
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cattle
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Cell Cycle Proteins
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Cell Line
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Cloning, Molecular
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DNA, Complementary
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Fungal Proteins / genetics
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G1 Phase* / drug effects
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Heat-Shock Proteins / metabolism*
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Humans
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Immunophilins*
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Molecular Sequence Data
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Phosphatidylinositol 3-Kinases*
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Polyenes / metabolism*
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Polyenes / pharmacology
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Proteins / analysis*
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Proteins / chemistry
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Proteins / genetics
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Recombinant Fusion Proteins / genetics
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae Proteins*
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Sequence Homology, Amino Acid
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Sirolimus
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TOR Serine-Threonine Kinases
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Tacrolimus Binding Proteins
Substances
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Carrier Proteins
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Cell Cycle Proteins
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DNA, Complementary
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Fungal Proteins
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Heat-Shock Proteins
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Polyenes
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Proteins
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Recombinant Fusion Proteins
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Saccharomyces cerevisiae Proteins
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Phosphotransferases (Alcohol Group Acceptor)
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MTOR protein, human
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TOR1 protein, S cerevisiae
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TOR2 protein, S cerevisiae
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TOR Serine-Threonine Kinases
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Tacrolimus Binding Proteins
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Immunophilins
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Sirolimus