PMID- 22457330
OWN - NLM
STAT- MEDLINE
DCOM- 20120808
LR  - 20240318
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 5
IP  - 217
DP  - 2012 Mar 27
TI  - Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular 
      carcinoma in mice.
PG  - ra24
LID - 10.1126/scisignal.2002739 [doi]
AB  - The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a 
      nutrient-sensitive protein kinase that is aberrantly activated in many human 
      cancers. Whether dysregulation of mTORC1 signaling in normal tissues increases 
      the risk for cancer, however, is unknown. We focused on hepatocellular carcinoma, 
      which has been linked to environmental factors that affect mTORC1 activity, 
      including diet. Ablation of the gene encoding TSC1 (tuberous sclerosis complex 
      1), which as part of the TSC1-TSC2 complex is an upstream inhibitor of mTORC1, 
      results in constitutively increased mTORC1 signaling, an effect on this pathway 
      similar to that of obesity. We found that mice with liver-specific knockout of 
      Tsc1 developed sporadic hepatocellular carcinoma with heterogeneous histological 
      and biochemical features. The spontaneous development of hepatocellular carcinoma 
      in this mouse model was preceded by a series of pathological changes that 
      accompany the primary etiologies of this cancer in humans, including liver 
      damage, inflammation, necrosis, and regeneration. Chronic mTORC1 signaling led to 
      unresolved endoplasmic reticulum stress and defects in autophagy, factors that 
      contributed to hepatocyte damage and hepatocellular carcinoma development. 
      Therefore, we conclude that increased activation of mTORC1 can promote 
      carcinogenesis and may thus represent a key molecular link between cancer risk 
      and environmental factors, such as diet.
FAU - Menon, Suchithra
AU  - Menon S
AD  - Department of Genetics and Complex Diseases, Harvard School of Public Health, 
      Boston, MA 02115, USA.
FAU - Yecies, Jessica L
AU  - Yecies JL
FAU - Zhang, Hui H
AU  - Zhang HH
FAU - Howell, Jessica J
AU  - Howell JJ
FAU - Nicholatos, Justin
AU  - Nicholatos J
FAU - Harputlugil, Eylul
AU  - Harputlugil E
FAU - Bronson, Roderick T
AU  - Bronson RT
FAU - Kwiatkowski, David J
AU  - Kwiatkowski DJ
FAU - Manning, Brendan D
AU  - Manning BD
LA  - eng
GR  - P01 CA120964/CA/NCI NIH HHS/United States
GR  - R01 CA122617/CA/NCI NIH HHS/United States
GR  - CA122617/CA/NCI NIH HHS/United States
GR  - CA120964/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 - 20120327
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Crtc1 protein, mouse)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proliferating Cell Nuclear Antigen)
RN  - 0 (Proteins)
RN  - 0 (TSC1 protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
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
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Autophagy/drug effects
MH  - Carcinoma, Hepatocellular/genetics/*metabolism/pathology
MH  - Cells, Cultured
MH  - Disease Progression
MH  - Endoplasmic Reticulum Stress/drug effects
MH  - Female
MH  - Hepatocytes/metabolism/pathology
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - Liver/metabolism/pathology/physiopathology
MH  - Liver Neoplasms/genetics/*metabolism/pathology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Multiprotein Complexes/metabolism
MH  - Proliferating Cell Nuclear Antigen/metabolism
MH  - Proteins/*metabolism
MH  - Signal Transduction/drug effects/genetics/physiology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/*metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tumor Suppressor Proteins/genetics/metabolism
PMC - PMC3743103
MID - NIHMS479354
EDAT- 2012/03/30 06:00
MHDA- 2012/08/09 06:00
PMCR- 2013/08/14
CRDT- 2012/03/30 06:00
PHST- 2012/03/30 06:00 [entrez]
PHST- 2012/03/30 06:00 [pubmed]
PHST- 2012/08/09 06:00 [medline]
PHST- 2013/08/14 00:00 [pmc-release]
AID - 5/217/ra24 [pii]
AID - 10.1126/scisignal.2002739 [doi]
PST - epublish
SO  - Sci Signal. 2012 Mar 27;5(217):ra24. doi: 10.1126/scisignal.2002739.