A Mammalian Protein Targeted by G1-arresting Rapamycin-Receptor Complex

Nature. 1994 Jun 30;369(6483):756-8. doi: 10.1038/369756a0.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Carrier Proteins / analysis
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cattle
  • Cell Cycle Proteins
  • Cell Line
  • Cloning, Molecular
  • DNA, Complementary
  • Fungal Proteins / genetics
  • G1 Phase* / drug effects
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Immunophilins*
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Polyenes / metabolism*
  • Polyenes / pharmacology
  • Proteins / analysis*
  • Proteins / chemistry
  • Proteins / genetics
  • Recombinant Fusion Proteins / genetics
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins*
  • Sequence Homology, Amino Acid
  • Sirolimus
  • TOR Serine-Threonine Kinases
  • Tacrolimus Binding Proteins

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA, Complementary
  • Fungal Proteins
  • Heat-Shock Proteins
  • Polyenes
  • Proteins
  • Recombinant Fusion Proteins
  • Saccharomyces cerevisiae Proteins
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • TOR1 protein, S cerevisiae
  • TOR2 protein, S cerevisiae
  • Tacrolimus Binding Proteins
  • Immunophilins
  • Sirolimus

Associated data

  • GENBANK/L34075