PMID- 22215663
OWN - NLM
STAT- MEDLINE
DCOM- 20120409
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 8
DP  - 2012 Feb 17
TI  - Functional RNA interference (RNAi) screen identifies system A neutral amino acid 
      transporter 2 (SNAT2) as a mediator of arsenic-induced endoplasmic reticulum 
      stress.
PG  - 6025-34
LID - 10.1074/jbc.M111.311217 [doi]
AB  - Exposure to the toxic metalloid arsenic is associated with diabetes and cancer 
      and causes proteotoxicity and endoplasmic reticulum (ER) stress at the cellular 
      level. Adaptive responses to ER stress are implicated in cancer and diabetes; 
      thus, understanding mechanisms of arsenic-induced ER stress may offer insights 
      into pathogenesis. Here, we identify genes required for arsenite-induced ER 
      stress response in a genome-wide RNAi screen. Using an shRNA library targeting 
       approximately 20,000 human genes, together with an ER stress cell model, we performed flow 
      cytometry-based cell sorting to isolate cells with defective response to 
      arsenite. Our screen discovered several genes modulating arsenite-induced ER 
      stress, including sodium-dependent neutral amino acid transporter, SNAT2. SNAT2 
      expression and activity are up-regulated by arsenite, in a manner dependent on 
      activating transcription factor 4 (ATF4), an important mediator of the integrated 
      stress response. Inhibition of SNAT2 expression or activity or deprivation of its 
      primary substrate, glutamine, specifically suppressed ER stress induced by 
      arsenite but not tunicamycin. Induction of SNAT2 is coincident with the 
      activation of the nutrient-sensing mammalian target of rapamycin (mTOR) pathway, 
      which is at least partially required for arsenite-induced ER stress. Importantly, 
      inhibition of the SNAT2 or the System L transporter, LAT1, suppressed mTOR 
      activation by arsenite, supporting a role for these transporters in modulating 
      amino acid signaling. These findings reveal SNAT2 as an important and specific 
      mediator of arsenic-induced ER stress, and suggest a role for aberrant mTOR 
      activation in arsenic-related human diseases. Furthermore, this study 
      demonstrates the utility of RNAi screens in elucidating cellular mechanisms of 
      environmental toxins.
FAU - Oh, Raymond S
AU  - Oh RS
AD  - Program in Molecular and Integrative Physiological Sciences, Harvard School of 
      Public Health, Boston, Massachusetts 02115, USA.
FAU - Pan, Wen-Chi
AU  - Pan WC
FAU - Yalcin, Abdullah
AU  - Yalcin A
FAU - Zhang, Hong
AU  - Zhang H
FAU - Guilarte, Tomas R
AU  - Guilarte TR
FAU - Hotamisligil, Gokhan S
AU  - Hotamisligil GS
FAU - Christiani, David C
AU  - Christiani DC
FAU - Lu, Quan
AU  - Lu Q
LA  - eng
GR  - DK052539/DK/NIDDK NIH HHS/United States
GR  - P30 ES000002/ES/NIEHS NIH HHS/United States
GR  - P42ES016454/ES/NIEHS NIH HHS/United States
GR  - P30ES000002/ES/NIEHS NIH HHS/United States
GR  - R01 DK052539/DK/NIDDK NIH HHS/United States
GR  - RC4 DK090942/DK/NIDDK NIH HHS/United States
GR  - P42 ES016454/ES/NIEHS NIH HHS/United States
GR  - DK090942/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120103
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (ATF4 protein, human)
RN  - 0 (Amino Acid Transport System A)
RN  - 0 (Arsenites)
RN  - 0 (Environmental Pollutants)
RN  - 0 (SLC38A2 protein, human)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - N5509X556J (arsenite)
RN  - N712M78A8G (Arsenic)
SB  - IM
MH  - Activating Transcription Factor 4/metabolism
MH  - Amino Acid Transport System A/deficiency/genetics/*metabolism
MH  - Arsenic/*toxicity
MH  - Arsenites/toxicity
MH  - Endoplasmic Reticulum Stress/*drug effects/*genetics
MH  - Environmental Pollutants/*toxicity
MH  - Gene Expression Regulation/drug effects/genetics
MH  - Genomics/*methods
MH  - HEK293 Cells
MH  - Humans
MH  - *RNA Interference
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC3285369
EDAT- 2012/01/05 06:00
MHDA- 2012/04/10 06:00
PMCR- 2013/02/17
CRDT- 2012/01/05 06:00
PHST- 2012/01/05 06:00 [entrez]
PHST- 2012/01/05 06:00 [pubmed]
PHST- 2012/04/10 06:00 [medline]
PHST- 2013/02/17 00:00 [pmc-release]
AID - S0021-9258(20)61256-X [pii]
AID - M111.311217 [pii]
AID - 10.1074/jbc.M111.311217 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Feb 17;287(8):6025-34. doi: 10.1074/jbc.M111.311217. Epub 2012 
      Jan 3.