PMID- 23599434
OWN - NLM
STAT- MEDLINE
DCOM- 20130806
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 22
DP  - 2013 May 31
TI  - Positive feedback regulation of human inducible nitric-oxide synthase expression 
      by Ras protein S-nitrosylation.
PG  - 15677-86
LID - 10.1074/jbc.M113.475319 [doi]
AB  - The production of nitric oxide (NO) by inducible NO synthase (iNOS) regulates 
      many aspects of physiology and pathology. The expression of iNOS needs to be 
      tightly regulated to balance the broad ranging properties of NO. We have 
      investigated the feedback regulation of cytokine-induced iNOS expression by NO in 
      human cells. The pharmacological inhibition of iNOS activity reduced iNOS protein 
      levels in response to cytokine stimulation in a human epithelial cell line (A549 
      cells) as well as in primary human astrocytes and bronchial epithelial cells. The 
      addition of exogenous NO using a NO donor prevented the reduction in iNOS levels 
      caused by blockade of iNOS activity. Examination of signaling pathways affected 
      by iNOS indicated that NO S-nitrosylated Ras. Transfection of cells with a 
      S-nitrosylation-resistant Ras mutant reduced iNOS protein levels, indicating a 
      role for this Ras modification in the amplification of iNOS levels. Further, the 
      induction of iNOS protein levels correlated with the late activation of the 
      phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin (mTOR) 
      pathways, and inhibition of these signaling molecules reduced iNOS levels. 
      Altogether, our findings reveal a previously unknown regulatory pathway that 
      amplifies iNOS expression in human cells.
FAU - Lee, Martin
AU  - Lee M
AD  - Department of Molecular Biology and Biochemistry, Simon Fraser University, 
      Burnaby, British Columbia V5A 1S6, Canada.
FAU - Choy, Jonathan C
AU  - Choy JC
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130418
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.13.39 (NOS2 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Cell Line
MH  - Enzyme Induction/physiology
MH  - Epithelial Cells/cytology/*metabolism
MH  - Humans
MH  - Nitric Oxide/genetics/*metabolism
MH  - Nitric Oxide Synthase Type II/*biosynthesis/genetics
MH  - Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Signal Transduction/*physiology
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
MH  - ras Proteins/genetics/*metabolism
PMC - PMC3668727
OTO - NOTNLM
OT  - Nitric Oxide
OT  - Nitric-oxide Synthase
OT  - Ras
OT  - S-Nitrosylation
OT  - Signal Transduction
EDAT- 2013/04/20 06:00
MHDA- 2013/08/07 06:00
PMCR- 2014/05/31
CRDT- 2013/04/20 06:00
PHST- 2013/04/20 06:00 [entrez]
PHST- 2013/04/20 06:00 [pubmed]
PHST- 2013/08/07 06:00 [medline]
PHST- 2014/05/31 00:00 [pmc-release]
AID - S0021-9258(20)45957-5 [pii]
AID - M113.475319 [pii]
AID - 10.1074/jbc.M113.475319 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 May 31;288(22):15677-86. doi: 10.1074/jbc.M113.475319. Epub 
      2013 Apr 18.