The TOR kinases link nutrient sensing to cell growth

被引:287
作者
Rohde, J
Heitman, J
Cardenas, ME
机构
[1] Duke Univ, Med Ctr, Dept Genet, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA
[3] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[4] Duke Univ, Med Ctr, Dept Microbiol, Durham, NC 27710 USA
[5] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA
关键词
D O I
10.1074/jbc.R000034200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Rapamycin is an immunosuppressive natural product that inhibits the proliferation of T-cells in response to nutrients and growth factors. Rapamycin binds to the peptidyl-prolyl isomerase FKBP12 and forms protein-drug complexes that inhibit signal transduction by the TOR kinases. The FKBP12 and TOR proteins are conserved from fungi to humans, and in both organisms the TOR signaling pathway plays a role in nutrient sensing. In response to nitrogen sources or amino acids, TOR regulates both transcription and translation, enabling cells to appropriately respond to growth-promoting signals. Rapamycin is having a profound impact on clinical medicine and was approved as an immunosuppressant for transplant recipients in 1999. Ongoing clinical studies address new clinical applications for rapamycin as an antiproliferative drug for chemotherapy and invasive cardiology.
引用
收藏
页码:9583 / 9586
页数:4
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共 74 条
  • [11] A MAMMALIAN PROTEIN TARGETED BY G1-ARRESTING RAPAMYCIN-RECEPTOR COMPLEX
    BROWN, EJ
    ALBERS, MW
    SHIN, TB
    ICHIKAWA, K
    KEITH, CT
    LANE, WS
    SCHREIBER, SL
    [J]. NATURE, 1994, 369 (6483) : 756 - 758
  • [12] A signaling pathway to translational control
    Brown, EJ
    Schreiber, SL
    [J]. CELL, 1996, 86 (04) : 517 - 520
  • [13] CONTROL OF P70 S6 KINASE BY KINASE-ACTIVITY OF FRAP IN-VIVO
    BROWN, EJ
    BEAL, PA
    KEITH, CT
    CHEN, J
    SHIN, TB
    SCHREIBER, SL
    [J]. NATURE, 1995, 377 (6548) : 441 - 446
  • [14] Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin
    Brunn, GJ
    Hudson, CC
    Sekulic, A
    Williams, JM
    Hosoi, H
    Houghton, PJ
    Lawrence, JC
    Abraham, RT
    [J]. SCIENCE, 1997, 277 (5322) : 99 - 101
  • [15] Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002
    Brunn, GJ
    Williams, J
    Sabers, C
    Wiederrecht, G
    Lawrence, JC
    Abraham, RT
    [J]. EMBO JOURNAL, 1996, 15 (19) : 5256 - 5267
  • [16] RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1
    Burnett, PE
    Barrow, RK
    Cohen, NA
    Snyder, SH
    Sabatini, DM
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (04) : 1432 - 1437
  • [17] DOMINANT MISSENSE MUTATIONS IN A NOVEL YEAST PROTEIN RELATED TO MAMMALIAN PHOSPHATIDYLINOSITOL 3-KINASE AND VPS34 ABROGATE RAPAMYCIN CYTOTOXICITY
    CAFFERKEY, R
    YOUNG, PR
    MCLAUGHLIN, MM
    BERGSMA, DJ
    KOLTIN, Y
    SATHE, GM
    FAUCETTE, L
    ENG, WK
    JOHNSON, RK
    LIVI, GP
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (10) : 6012 - 6023
  • [18] The TOR signaling cascade regulates gene expression in response to nutrients
    Cardenas, ME
    Cutler, NS
    Lorenz, MC
    Di Como, CJ
    Heitman, J
    [J]. GENES & DEVELOPMENT, 1999, 13 (24) : 3271 - 3279
  • [19] FKBP12-RAPAMYCIN TARGET TOR2 IS A VACUOLAR PROTEIN WITH AN ASSOCIATED PHOSPHATIDYLINOSITOL-4 KINASE-ACTIVITY
    CARDENAS, ME
    HEITMAN, J
    [J]. EMBO JOURNAL, 1995, 14 (23) : 5892 - 5907
  • [20] IDENTIFICATION OF AN 11-KDA FKBP12-RAPAMYCIN-BINDING DOMAIN WITHIN THE 289-KDA FKBP12-RAPAMYCIN-ASSOCIATED PROTEIN AND CHARACTERIZATION OF A CRITICAL SERINE RESIDUE
    CHEN, J
    ZHENG, XF
    BROWN, EJ
    SCHREIBER, SL
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (11) : 4947 - 4951