PMID- 23108404
OWN - NLM
STAT- MEDLINE
DCOM- 20131115
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 32
IP  - 39
DP  - 2013 Sep 26
TI  - mTORC1 enhancement of STIM1-mediated store-operated Ca2+ entry constrains 
      tuberous sclerosis complex-related tumor development.
PG  - 4702-11
LID - 10.1038/onc.2012.481 [doi]
AB  - The protein complex of tuberous sclerosis complex (TSC)1 and TSC2 tumor 
      suppressors is a key negative regulator of mammalian target of rapamycin (mTOR). 
      Hyperactive mTOR signaling due to the loss-of-function of mutations in either 
      TSC1 or TSC2 gene causes TSC, an autosomal dominant disorder featured with benign 
      tumors in multiple organs. As the ubiquitous second messenger calcium (Ca(2+)) 
      regulates various cellular processes involved in tumorigenesis, we explored the 
      potential role of mTOR in modulation of cellular Ca(2+) homeostasis, and in turn 
      the effect of Ca(2+) signaling in TSC-related tumor development. We found that 
      loss of Tsc2 potentiated store-operated Ca(2+) entry (SOCE) in an mTOR complex 1 
      (mTORC1)-dependent way. The endoplasmic reticulum Ca(2+) sensor, stromal 
      interaction molecule 1 (STIM1), was upregulated in Tsc2-deficient cells, and was 
      suppressed by mTORC1 inhibitor rapamycin. In addition, SOCE repressed AKT1 
      phosphorylation. Blocking SOCE either by depleting STIM1 or ectopically 
      expressing dominant-negative Orai1 accelerated TSC-related tumor development, 
      likely because of restored AKT1 activity and enhanced tumor angiogenesis. Our 
      data, therefore, suggest that mTORC1 enhancement of store-operated Ca(2+) 
      signaling hinders TSC-related tumor growth through suppression of AKT1 signaling. 
      The augmented SOCE by hyperactive mTORC1-STIM1 cascade may contribute to the 
      benign nature of TSC-related tumors. Application of SOCE agonists could thus be a 
      contraindication for TSC patients. In contrast, SOCE agonists should attenuate 
      mTOR inhibitors-mediated AKT reactivation and consequently potentiate their 
      efficacy in the treatment of the patients with TSC.
FAU - Peng, H
AU  - Peng H
AD  - Department of Physiology and Pathophysiology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences and School of Basic 
      Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 
      Beijing, China.
FAU - Liu, J
AU  - Liu J
FAU - Sun, Q
AU  - Sun Q
FAU - Chen, R
AU  - Chen R
FAU - Wang, Y
AU  - Wang Y
FAU - Duan, J
AU  - Duan J
FAU - Li, C
AU  - Li C
FAU - Li, B
AU  - Li B
FAU - Jing, Y
AU  - Jing Y
FAU - Chen, X
AU  - Chen X
FAU - Mao, Q
AU  - Mao Q
FAU - Xu, K-F
AU  - Xu KF
FAU - Walker, C L
AU  - Walker CL
FAU - Li, J
AU  - Li J
FAU - Wang, J
AU  - Wang J
FAU - Zhang, H
AU  - Zhang H
LA  - eng
GR  - R01 CA143811/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121029
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Calcium Channels)
RN  - 0 (Membrane Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (ORAI1 Protein)
RN  - 0 (ORAI1 protein, human)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (STIM1 protein, human)
RN  - 0 (Stromal Interaction Molecule 1)
RN  - 0 (TRAF3IP2 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tsc2 protein, rat)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Necrosis Factor Receptor-Associated Peptides and Proteins)
RN  - 0 (Tumor Suppressor Proteins)
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 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Calcium Channels/genetics/physiology
MH  - Calcium Signaling/*physiology
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - *Cell Transformation, Neoplastic
MH  - Female
MH  - Fibroblasts
MH  - Humans
MH  - Kidney Neoplasms/genetics/pathology
MH  - Leiomyoma/pathology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Membrane Proteins/*physiology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Multiprotein Complexes/*physiology
MH  - Neoplasm Proteins/*physiology
MH  - Neovascularization, Pathologic/physiopathology
MH  - ORAI1 Protein
MH  - Phosphorylation
MH  - Protein Processing, Post-Translational
MH  - RNA Interference
MH  - Rats
MH  - Recombinant Fusion Proteins/physiology
MH  - Stromal Interaction Molecule 1
MH  - TOR Serine-Threonine Kinases/*physiology
MH  - Tuberous Sclerosis/genetics/metabolism/*pathology
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism
MH  - Tumor Suppressor Proteins/physiology
MH  - Uterine Neoplasms/pathology
PMC - PMC3931471
MID - NIHMS553304
COIS- CONFLICT OF INTEREST The authors declare no conflict of interest.
EDAT- 2012/10/31 06:00
MHDA- 2013/11/16 06:00
PMCR- 2014/02/21
CRDT- 2012/10/31 06:00
PHST- 2012/02/17 00:00 [received]
PHST- 2012/08/27 00:00 [revised]
PHST- 2012/09/02 00:00 [accepted]
PHST- 2012/10/31 06:00 [entrez]
PHST- 2012/10/31 06:00 [pubmed]
PHST- 2013/11/16 06:00 [medline]
PHST- 2014/02/21 00:00 [pmc-release]
AID - onc2012481 [pii]
AID - 10.1038/onc.2012.481 [doi]
PST - ppublish
SO  - Oncogene. 2013 Sep 26;32(39):4702-11. doi: 10.1038/onc.2012.481. Epub 2012 Oct 
      29.