PMID- 19150980
OWN - NLM
STAT- MEDLINE
DCOM- 20090514
LR  - 20240416
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 284
IP  - 12
DP  - 2009 Mar 20
TI  - An ATP-competitive mammalian target of rapamycin inhibitor reveals 
      rapamycin-resistant functions of mTORC1.
PG  - 8023-32
LID - 10.1074/jbc.M900301200 [doi]
AB  - The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two 
      functionally distinct complexes, mTORC1 and mTORC2, that coordinately promote 
      cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1 
      inhibitor with clinical applications as an immunosuppressant and anti-cancer 
      agent. Here we find that Torin1, a highly potent and selective ATP-competitive 
      mTOR inhibitor that directly inhibits both complexes, impairs cell growth and 
      proliferation to a far greater degree than rapamycin. Surprisingly, these effects 
      are independent of mTORC2 inhibition and are instead because of suppression of 
      rapamycin-resistant functions of mTORC1 that are necessary for cap-dependent 
      translation and suppression of autophagy. These effects are at least partly 
      mediated by mTORC1-dependent and rapamycin-resistant phosphorylation of 4E-BP1. 
      Our findings challenge the assumption that rapamycin completely inhibits mTORC1 
      and indicate that direct inhibitors of mTORC1 kinase activity may be more 
      successful than rapamycin at inhibiting tumors that depend on mTORC1.
FAU - Thoreen, Carson C
AU  - Thoreen CC
AD  - Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
FAU - Kang, Seong A
AU  - Kang SA
FAU - Chang, Jae Won
AU  - Chang JW
FAU - Liu, Qingsong
AU  - Liu Q
FAU - Zhang, Jianming
AU  - Zhang J
FAU - Gao, Yi
AU  - Gao Y
FAU - Reichling, Laurie J
AU  - Reichling LJ
FAU - Sim, Taebo
AU  - Sim T
FAU - Sabatini, David M
AU  - Sabatini DM
FAU - Gray, Nathanael S
AU  - Gray NS
LA  - eng
GR  - R01 CA103866/CA/NCI NIH HHS/United States
GR  - R01 CA129105/CA/NCI NIH HHS/United States
GR  - R01 CA129105-03/CA/NCI NIH HHS/United States
GR  - R01 AI47389/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20090115
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (RNA Caps)
RN  - 0 (Transcription Factors)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
EIN - J Biol Chem. 2020 Feb 28;295(9):2886. PMID: 32111721
MH  - Adaptor Proteins, Signal Transducing
MH  - Adenosine Triphosphate/*metabolism
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Autophagy/drug effects
MH  - Carrier Proteins/*metabolism
MH  - Cell Cycle Proteins
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Eukaryotic Initiation Factors
MH  - Immunosuppressive Agents/pharmacology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Knockout
MH  - Multienzyme Complexes/antagonists & inhibitors/*metabolism
MH  - Multiprotein Complexes
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation/drug effects
MH  - Phosphotransferases (Alcohol Group Acceptor)/*metabolism
MH  - Protein Biosynthesis/drug effects
MH  - Proteins
MH  - RNA Caps/metabolism
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/antagonists & inhibitors/*metabolism
PMC - PMC2658096
EDAT- 2009/01/20 09:00
MHDA- 2009/05/15 09:00
PMCR- 2010/03/20
CRDT- 2009/01/20 09:00
PHST- 2009/01/20 09:00 [entrez]
PHST- 2009/01/20 09:00 [pubmed]
PHST- 2009/05/15 09:00 [medline]
PHST- 2010/03/20 00:00 [pmc-release]
AID - S0021-9258(20)32515-1 [pii]
AID - 8023 [pii]
AID - 10.1074/jbc.M900301200 [doi]
PST - ppublish
SO  - J Biol Chem. 2009 Mar 20;284(12):8023-32. doi: 10.1074/jbc.M900301200. Epub 2009 
      Jan 15.