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A mammalian protein targeted by G1-arresting rapamycin–receptor complex

Abstract

THE structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways1,2. FKBP12–rapamycin inhibits progression through the Gl phase of the cell cycle in osteosarcoma3, liver4, 5 and T cells6, 7 as well as in yeast8 and interferes with mitogenic signalling pathways that are involved in Gl progression9, 10 namely with activation of the protein p70S6k (refs 5,11–13) and cyclin-dependent kinases3, 14–16. 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 cerevisiae8, 17, 18. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP–rapamycin complex directly17, 19 these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases17–20.

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References

  1. 1

    Schreiber, S. L. Science 251, 283–287 (1991).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Schreiber, S. L. Cell 70, 365–368 (1992).

    CAS  Article  Google Scholar 

  3. 3

    Albers, M. W. et al. Ann. N. Y. Acad. Sci. 696, 54–62 (1993).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Francavilla, A. et al. Hepatology 15, 871–877 (1992).

    CAS  Article  Google Scholar 

  5. 5

    Price, D. J., Grove, J. R., Calvo, V., Avruch, J. & Bierer, B. E. Science 257, 973–977 (1992).

    ADS  CAS  Article  Google Scholar 

  6. 6

    Bierer, B. E. et al. Proc. natn. Acad. Sci. U.S.A. 87, 9231–9235 (1990).

    ADS  CAS  Article  Google Scholar 

  7. 7

    Dumont, F. J., Staruch, M. J., Koprak, S. L., Mclino, M. R. & Sigal, N. H. J. Immun. 144, 251–258 (1990).

    CAS  PubMed  Google Scholar 

  8. 8

    Heitman, J., Movva, N. R. & Hall, M. N. Science 253, 905–909 (1991).

    ADS  CAS  Article  Google Scholar 

  9. 9

    Lane, H. A., Fernandez, A., Lamb, N. J. C. & Thomas, G. Nature 363, 170–172 (1993).

    ADS  CAS  Article  Google Scholar 

  10. 10

    Norbury C. & Nurse, P. A. Rev. Biochem. 61, 441–470 (1992).

    CAS  Article  Google Scholar 

  11. 11

    Chung, J., Kuo, C. J., Crabtree, G. R. & Blenis, J. Cell 69, 1227–1236 (1992).

    CAS  Article  Google Scholar 

  12. 12

    Kuo, C. J. et al. Nature 358, 70–73 (1992).

    ADS  CAS  Article  Google Scholar 

  13. 13

    Calvo, V., Crews, C. M., Vik, T. A. & Bierer, B. Proc. natn. Acad Sci. U.S.A 89, 7571–7575 (1992).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Morice, W. G., Wiederrecht, G., Brunn, G. J., Siekierka, J. J. & Abraham, R. T. J. biol. Chem. 268, 22737–22745 (1993).

    CAS  PubMed  Google Scholar 

  15. 15

    Morice, W. G., Brunn, G. J., Wiederrecht, G., Siekierka, J. J. & Abraham, R. T. J. biol. Chem. 268, 3734–3738 (1993).

    CAS  PubMed  Google Scholar 

  16. 16

    Albers, M. W. et al. J. biol. Chem. 268, 22825–22829 (1993).

    CAS  PubMed  Google Scholar 

  17. 17

    Cafferkey, R. et al. Molec. cell. Biol. 13, 6012–6023 (1993).

    CAS  Article  Google Scholar 

  18. 18

    Kunz, J. et al. Cell 73, 585–596 (1993).

    CAS  Article  Google Scholar 

  19. 19

    Helliwell, S. B. et al. Molec. Biol. Cell 5, 105–118 (1994).

    CAS  Article  Google Scholar 

  20. 20

    Flanagan, C. A. et al. Science 262, 1444–1448 (1993).

    ADS  CAS  Article  Google Scholar 

  21. 21

    Hayward, C. M., Yohannes, D. & Danishefsky, S. J. J. Am. chem. Soc. 115, 9345–9346 (1993).

    CAS  Article  Google Scholar 

  22. 22

    Hultsch, T., Martin, R. & Hohman, R. J. Molec. Biol. Cell. 3, 981–987 (1992).

    CAS  Article  Google Scholar 

  23. 23

    Galat, A., Lane, W. S., Standaert, R. F. & Schreiber, S. L. Biochemistry 31, 2427–2434 (1992).

    CAS  Article  Google Scholar 

  24. 24

    Foor, F. et al. Nature 360, 682–684 (1992).

    ADS  CAS  Article  Google Scholar 

  25. 25

    Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning A Laboratory Manual, 2nd edn (Cold Spring Harbor Laboratory Press, New York, 1989).

    Google Scholar 

  26. 26

    Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. J. molec. Biol. 215, 403–410 (1990).

    CAS  Article  Google Scholar 

  27. 27

    Devereux, J., Haeberli, P. & Smithies, O. Nucleic Acids Res. 12, 387–395 (1984).

    CAS  Article  Google Scholar 

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Brown, E., Albers, M., Bum Shin, T. et al. A mammalian protein targeted by G1-arresting rapamycin–receptor complex. Nature 369, 756–758 (1994). https://doi.org/10.1038/369756a0

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