PMID- 20176935
OWN - NLM
STAT- MEDLINE
DCOM- 20100512
LR  - 20211203
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 10
DP  - 2010 Mar 9
TI  - Cholesterol trafficking is required for mTOR activation in endothelial cells.
PG  - 4764-9
LID - 10.1073/pnas.0910872107 [doi]
AB  - Mammalian target of rapamycin (mTOR) constitutes a nodal point of a signaling 
      network that regulates cell growth and proliferation in response to various 
      environmental cues ranging from growth factor stimulation to nutrients to stress. 
      Whether mTOR is also affected by cholesterol homeostasis, however, has remained 
      unknown. We report that blockade of cholesterol trafficking through lysosome by a 
      newly identified inhibitor of angiogenesis, itraconazole, leads to inhibition of 
      mTOR activity in endothelial cells. Inhibition of mTOR by itraconazole but not 
      rapamycin can be partially restored by extracellular cholesterol delivered by 
      cyclodextrin. Moreover, other known inhibitors of endosomal/lysosomal cholesterol 
      trafficking as well as siRNA knockdown of Niemann-Pick disease type C (NPC) 1 and 
      NPC2 also cause inhibition of mTOR in endothelial cells. In addition, both the 
      accumulation of cholesterol in the lysosome and inhibition of mTOR caused by 
      itraconazole can be reversed by thapsigarin. These observations suggest that mTOR 
      is likely to be involved in sensing membrane sterol concentrations in endothelial 
      cells, and the cholesterol trafficking pathway is a promising target for the 
      discovery of inhibitors of angiogenesis.
FAU - Xu, Jing
AU  - Xu J
AD  - Department of Pharmacology and Oncology, The Johns Hopkins School of Medicine, 
      Baltimore, MD 21205, USA.
FAU - Dang, Yongjun
AU  - Dang Y
FAU - Ren, Yunzhao R
AU  - Ren YR
FAU - Liu, Jun O
AU  - Liu JO
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100222
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Androstenes)
RN  - 0 (CDKN1A protein, human)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Cyclodextrins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (NPC1 protein, human)
RN  - 0 (Niemann-Pick C1 Protein)
RN  - 0 (Proteins)
RN  - 0 (Transcription Factors)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
RN  - 3039-71-2 (3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one)
RN  - 304NUG5GF4 (Itraconazole)
RN  - 67526-95-8 (Thapsigargin)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - OGG85SX4E4 (Imipramine)
SB  - IM
MH  - Androstenes/pharmacology
MH  - Biological Transport
MH  - Blotting, Western
MH  - Carrier Proteins/genetics/metabolism
MH  - Cell Cycle/drug effects
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Cholesterol/*metabolism/pharmacology
MH  - Cyclin-Dependent Kinase Inhibitor p21/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p27/metabolism
MH  - Cyclodextrins/pharmacology
MH  - Endothelial Cells/cytology/drug effects/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Imipramine/pharmacology
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Itraconazole/pharmacology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Membrane Glycoproteins/genetics/metabolism
MH  - Multiprotein Complexes
MH  - Niemann-Pick C1 Protein
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proteins
MH  - RNA Interference
MH  - TOR Serine-Threonine Kinases
MH  - Thapsigargin/pharmacology
MH  - Transcription Factors/metabolism
PMC - PMC2842052
COIS- The authors declare no conflict of interest.
EDAT- 2010/02/24 06:00
MHDA- 2010/05/13 06:00
PMCR- 2010/09/09
CRDT- 2010/02/24 06:00
PHST- 2010/02/24 06:00 [entrez]
PHST- 2010/02/24 06:00 [pubmed]
PHST- 2010/05/13 06:00 [medline]
PHST- 2010/09/09 00:00 [pmc-release]
AID - 0910872107 [pii]
AID - 200910872 [pii]
AID - 10.1073/pnas.0910872107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4764-9. doi: 
      10.1073/pnas.0910872107. Epub 2010 Feb 22.