PMID- 18988672
OWN - NLM
STAT- MEDLINE
DCOM- 20090324
LR  - 20191003
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 150
IP  - 3
DP  - 2009 Mar
TI  - S-glutathionylation impairs signal transducer and activator of transcription 3 
      activation and signaling.
PG  - 1122-31
LID - 10.1210/en.2008-1241 [doi]
AB  - S-glutathionylation is a physiological, reversible protein modification of 
      cysteine residues with glutathione in response to mild oxidative stress. Because 
      the key cell growth regulator signal transducer and activator of transcription 
      (STAT) 3 is particularly susceptible to redox regulation, we hypothesized that 
      oxidative modification of cysteine residues of STAT3 by S-glutathionylation may 
      occur. Herein, we show that the cysteine residues of STAT3 are modified by a 
      thiol-alkylating agent and are the targets of S-glutathionylation. STAT3 protein 
      thiol reactivity was reversibly attenuated with concomitant increase in the 
      S-glutathionylation of STAT3 upon treatment of human HepG2 hepatoma cells with 
      pyrrolidine dithiocarbamate, glutathione disulfide, or diamide. Under these 
      conditions there was a marked reduction in IL-6-dependent STAT3 signaling, 
      including decreased STAT3 tyrosine phosphorylation, loss in nuclear accumulation 
      of STAT3, and impaired expression of target genes, such as fibrinogen-gamma. In a 
      cell-free system, diamide induced glutathionylation of STAT3, which was decreased 
      upon addition of glutaredoxin (GRX)-1, a deglutathionylation enzyme, or the 
      reducing agent, dithiothreitol. Glutathionylated STAT3 was a poor Janus protein 
      tyrosine kinase 2 substrate in vitro, and it exhibited low DNA-binding activity. 
      Cellular GRX-1 activity was inhibited by diamide and pyrrolidine dithiocarbamate 
      treatment; however, ectopic expression of GRX-1 was accompanied by a modest 
      increase in phosphorylation, nuclear translocation, and DNA-binding ability of 
      STAT3 in response to IL-6. These results are the first to show 
      S-glutathionylation of STAT3, a modification that may exert regulatory function 
      in STAT3 signaling.
FAU - Xie, Yi
AU  - Xie Y
AD  - Laboratories of Clinical Investigation, National Institute on Aging, National 
      Institutes of Health, Baltimore, Maryland 21224, USA.
FAU - Kole, Sutapa
AU  - Kole S
FAU - Precht, Patricia
AU  - Precht P
FAU - Pazin, Michael J
AU  - Pazin MJ
FAU - Bernier, Michel
AU  - Bernier M
LA  - eng
GR  - ZIA AG000378-02/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20081106
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Antioxidants)
RN  - 0 (Diamines)
RN  - 0 (GLRX protein, human)
RN  - 0 (Glutaredoxins)
RN  - 0 (Interleukin-6)
RN  - 0 (Oxidants)
RN  - 0 (Pyrrolidines)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Thiocarbamates)
RN  - 25769-03-3 (pyrrolidine dithiocarbamic acid)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - GAN16C9B8O (Glutathione)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Antioxidants/pharmacology
MH  - Cells, Cultured
MH  - Cysteine/metabolism
MH  - Diamines/pharmacology
MH  - Glutaredoxins/genetics/metabolism/physiology
MH  - Glutathione/*metabolism
MH  - Humans
MH  - Interleukin-6/pharmacology
MH  - Janus Kinase 2/metabolism
MH  - Oxidants/pharmacology
MH  - Phosphorylation
MH  - Protein Processing, Post-Translational/drug effects/*physiology
MH  - Pyrrolidines/pharmacology
MH  - STAT3 Transcription Factor/*metabolism/physiology
MH  - Signal Transduction/physiology
MH  - Thiocarbamates/pharmacology
MH  - Transfection
PMC - PMC2654735
EDAT- 2008/11/08 09:00
MHDA- 2009/03/25 09:00
PMCR- 2010/03/01
CRDT- 2008/11/08 09:00
PHST- 2008/11/08 09:00 [pubmed]
PHST- 2009/03/25 09:00 [medline]
PHST- 2008/11/08 09:00 [entrez]
PHST- 2010/03/01 00:00 [pmc-release]
AID - en.2008-1241 [pii]
AID - 4604 [pii]
AID - 10.1210/en.2008-1241 [doi]
PST - ppublish
SO  - Endocrinology. 2009 Mar;150(3):1122-31. doi: 10.1210/en.2008-1241. Epub 2008 Nov 
      6.