PMID- 25652038
OWN - NLM
STAT- MEDLINE
DCOM- 20151214
LR  - 20220321
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 14
IP  - 2
DP  - 2015 Apr
TI  - Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of 
      FK506-binding proteins.
PG  - 265-73
LID - 10.1111/acel.12313 [doi]
AB  - The mechanism by which the drug rapamycin inhibits the mechanistic target of 
      rapamycin (mTOR) is of intense interest because of its likely relevance in cancer 
      biology, aging, and other age-related diseases. While rapamycin acutely and 
      directly inhibits mTORC1, only chronic administration of rapamycin can inhibit 
      mTORC2 in some, but not all, cell lines or tissues. The mechanism leading to cell 
      specificity of mTORC2 inhibition by rapamycin is not understood and is especially 
      important because many of the negative metabolic side effects of rapamycin, 
      reported in mouse studies and human clinical trials, have been attributed 
      recently to mTORC2 inhibition. Here, we identify the expression level of 
      different FK506-binding proteins (FKBPs), primarily FKBP12 and FKBP51, as the key 
      determinants for rapamycin-mediated inhibition of mTORC2. In support, enforced 
      reduction of FKBP12 completely converts a cell line that is sensitive to mTORC2 
      inhibition to an insensitive cell line, and increased expression can enhance 
      mTORC2 inhibition. Further reduction of FKBP12 in cell lines with already low 
      FKBP12 levels completely blocks mTORC1 inhibition by rapamycin, indicating that 
      relative FKBP12 levels are critical for both mTORC1 and mTORC2 inhibition, but at 
      different levels. In contrast, reduction of FKBP51 renders cells more sensitive 
      to mTORC2 inhibition. Our findings reveal that the expression of FKBP12 and 
      FKBP51 is the rate limiting factor that determines the responsiveness of a cell 
      line or tissue to rapamycin. These findings have implications for treating 
      specific diseases, including neurodegeneration and cancer, as well as targeting 
      aging in general.
CI  - (c) 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley 
      & Sons Ltd.
FAU - Schreiber, Katherine H
AU  - Schreiber KH
AD  - The Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, 
      USA.
FAU - Ortiz, Denise
AU  - Ortiz D
FAU - Academia, Emmeline C
AU  - Academia EC
FAU - Anies, Arieanna C
AU  - Anies AC
FAU - Liao, Chen-Yu
AU  - Liao CY
FAU - Kennedy, Brian K
AU  - Kennedy BK
LA  - eng
GR  - F32GM103149/GM/NIGMS NIH HHS/United States
GR  - R01AG033373/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150204
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Multiprotein Complexes)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 5.2.1.- (Tacrolimus Binding Proteins)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Age Factors
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Multiprotein Complexes/*antagonists & inhibitors/metabolism
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Tacrolimus Binding Proteins/*biosynthesis/metabolism
PMC - PMC4364838
OTO - NOTNLM
OT  - FKBP
OT  - aging
OT  - mTOR
OT  - rapamycin
EDAT- 2015/02/06 06:00
MHDA- 2015/12/15 06:00
PMCR- 2015/04/01
CRDT- 2015/02/06 06:00
PHST- 2014/12/12 00:00 [accepted]
PHST- 2015/02/06 06:00 [entrez]
PHST- 2015/02/06 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PHST- 2015/04/01 00:00 [pmc-release]
AID - 10.1111/acel.12313 [doi]
PST - ppublish
SO  - Aging Cell. 2015 Apr;14(2):265-73. doi: 10.1111/acel.12313. Epub 2015 Feb 4.