PMID- 22367541
OWN - NLM
STAT- MEDLINE
DCOM- 20120619
LR  - 20220727
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 485
IP  - 7396
DP  - 2012 Feb 22
TI  - The translational landscape of mTOR signalling steers cancer initiation and 
      metastasis.
PG  - 55-61
LID - 10.1038/nature10912 [doi]
AB  - The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein 
      synthesis that couples nutrient sensing to cell growth and cancer. However, the 
      downstream translationally regulated nodes of gene expression that may direct 
      cancer development are poorly characterized. Using ribosome profiling, we uncover 
      specialized translation of the prostate cancer genome by oncogenic mTOR 
      signalling, revealing a remarkably specific repertoire of genes involved in cell 
      proliferation, metabolism and invasion. We extend these findings by functionally 
      characterizing a class of translationally controlled pro-invasion messenger RNAs 
      that we show direct prostate cancer invasion and metastasis downstream of 
      oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site 
      inhibitor of mTOR, INK128, which reprograms this gene expression signature with 
      therapeutic benefit for prostate cancer metastasis, for which there is presently 
      no cure. Together, these findings extend our understanding of how the 'cancerous' 
      translation machinery steers specific cancer cell behaviours, including 
      metastasis, and may be therapeutically targeted.
FAU - Hsieh, Andrew C
AU  - Hsieh AC
AD  - School of Medicine and Department of Urology, Helen Diller Family Comprehensive 
      Cancer Center, University of California, San Francisco, California 94158, USA.
FAU - Liu, Yi
AU  - Liu Y
FAU - Edlind, Merritt P
AU  - Edlind MP
FAU - Ingolia, Nicholas T
AU  - Ingolia NT
FAU - Janes, Matthew R
AU  - Janes MR
FAU - Sher, Annie
AU  - Sher A
FAU - Shi, Evan Y
AU  - Shi EY
FAU - Stumpf, Craig R
AU  - Stumpf CR
FAU - Christensen, Carly
AU  - Christensen C
FAU - Bonham, Michael J
AU  - Bonham MJ
FAU - Wang, Shunyou
AU  - Wang S
FAU - Ren, Pingda
AU  - Ren P
FAU - Martin, Michael
AU  - Martin M
FAU - Jessen, Katti
AU  - Jessen K
FAU - Feldman, Morris E
AU  - Feldman ME
FAU - Weissman, Jonathan S
AU  - Weissman JS
FAU - Shokat, Kevan M
AU  - Shokat KM
FAU - Rommel, Christian
AU  - Rommel C
FAU - Ruggero, Davide
AU  - Ruggero D
LA  - eng
SI  - GEO/GSE35469
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - R01 CA140456/CA/NCI NIH HHS/United States
GR  - R01 CA154916/CA/NCI 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 - 20120222
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Benzoxazoles)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Phosphoproteins)
RN  - 0 (Pyrimidines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Repressor Proteins)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - JGH0DF1U03 (sapanisertib)
SB  - IM
CIN - Nature. 2012 May 3;485(7396):50-1. PMID: 22552093
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Benzoxazoles/pharmacology
MH  - Cell Cycle Proteins
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects/genetics
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Eukaryotic Initiation Factors/metabolism
MH  - Gene Expression Regulation, Neoplastic/drug effects/genetics
MH  - Genome/genetics
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neoplasm Invasiveness/genetics
MH  - *Neoplasm Metastasis/drug therapy/genetics
MH  - Phosphoproteins/metabolism
MH  - Prostatic Neoplasms/drug therapy/genetics/*pathology
MH  - *Protein Biosynthesis
MH  - Pyrimidines/pharmacology
MH  - RNA, Messenger/genetics/metabolism
MH  - Repressor Proteins/metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
PMC - PMC3663483
MID - NIHMS472851
EDAT- 2012/03/01 06:00
MHDA- 2012/06/20 06:00
PMCR- 2013/05/24
CRDT- 2012/02/28 06:00
PHST- 2011/07/14 00:00 [received]
PHST- 2012/02/03 00:00 [accepted]
PHST- 2012/02/28 06:00 [entrez]
PHST- 2012/03/01 06:00 [pubmed]
PHST- 2012/06/20 06:00 [medline]
PHST- 2013/05/24 00:00 [pmc-release]
AID - nature10912 [pii]
AID - 10.1038/nature10912 [doi]
PST - epublish
SO  - Nature. 2012 Feb 22;485(7396):55-61. doi: 10.1038/nature10912.