PMID- 20104019
OWN - NLM
STAT- MEDLINE
DCOM- 20100706
LR  - 20230926
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Linking)
VI  - 6
IP  - 2
DP  - 2010 Feb
TI  - ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy.
PG  - 239-47
AB  - Disturbance to endoplasmic reticulum (ER) homeostasis that cannot be rescued by 
      the unfolded protein response (UPR) results in autophagy and cell death, but the 
      precise mechanism was largely unknown. Here we demonstrated that ER 
      stress-induced cell death was mediated by autophagy which was partly attributed 
      to the inactivation of the mammalian target of rapamycin (mTOR). Three widely 
      used ER stress inducers including tunicamycin, DTT and MG132 led to the 
      conversion of LC3-I to LC3-II , a commonly used marker of autophagy, as well as 
      the downregulation of mTOR concurrently. TSC -deficient cells with constitutive 
      activation of mTOR exhibited more resistance to ER stress-induced autophagy, 
      compared with their wild-type counterparts. Furthermore, our studies showed that 
      ER stress-induced deactivation of mTOR was attributed to the downregulation of 
      AKT/TSC /mTOR pathway. Phosphatase and tensin homolog (PTEN) and AMP-activated 
      protein kinase (AMPK) as two regulators in this pathway seemed to be absent in 
      this regulation. As a chemical chaperone helping the correct folding of proteins, 
      4-phenylbutyric acid (4-PBA) partly rescued the AKT/TSC/mTOR pathway in 
      drug-induced acute ER stress. Moreover, constitutively-activated mTOR-induced 
      long-term ER stress attenuated the RTK/PI3K/AKT signaling pathway in response to 
      the stimulation by various growth factors, which could also be partly restored by 
      4-PBA.
FAU - Qin, Liang
AU  - Qin L
AD  - Department of Physiology, Institute of Basic Medical Sciences & School of Basic 
      Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 
      Beijing, China. liangqin2@gmail.com
FAU - Wang, Zheng
AU  - Wang Z
FAU - Tao, Lianyuan
AU  - Tao L
FAU - Wang, Yun
AU  - Wang Y
LA  - eng
PT  - Journal Article
DEP - 20100301
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (IRS1 protein, human)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Leupeptins)
RN  - 0 (Phenylbutyrates)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 7WY7YBI87E (4-phenylbutyric acid)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.1 (Receptors, Platelet-Derived Growth Factor)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Autophagy/*physiology
MH  - Cells, Cultured
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Endoplasmic Reticulum/drug effects/*metabolism
MH  - Fibroblasts/cytology/drug effects/physiology
MH  - Humans
MH  - Insulin Receptor Substrate Proteins/metabolism
MH  - Intracellular Signaling Peptides and Proteins/genetics/*metabolism
MH  - Leupeptins/pharmacology
MH  - Mice
MH  - Mice, Knockout
MH  - Phenylbutyrates/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/*metabolism
MH  - Receptors, Platelet-Derived Growth Factor/metabolism
MH  - Signal Transduction/*physiology
MH  - Stress, Physiological
MH  - TOR Serine-Threonine Kinases
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/genetics/*metabolism
EDAT- 2010/01/28 06:00
MHDA- 2010/07/07 06:00
CRDT- 2010/01/28 06:00
PHST- 2010/01/28 06:00 [entrez]
PHST- 2010/01/28 06:00 [pubmed]
PHST- 2010/07/07 06:00 [medline]
AID - 11062 [pii]
AID - 10.4161/auto.6.2.11062 [doi]
PST - ppublish
SO  - Autophagy. 2010 Feb;6(2):239-47. doi: 10.4161/auto.6.2.11062. Epub 2010 Mar 1.