PMID- 16246840
OWN - NLM
STAT- MEDLINE
DCOM- 20060404
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 280
IP  - 51
DP  - 2005 Dec 23
TI  - Nitric oxide negatively regulates Fas CD95-induced apoptosis through inhibition 
      of ubiquitin-proteasome-mediated degradation of FLICE inhibitory protein.
PG  - 42044-50
AB  - Stimulation of cell surface Fas (CD95) results in recruitment of cytoplasmic 
      proteins and activation of caspase-8, which in turn activates downstream effector 
      caspases leading to programmed cell death. Nitric oxide (NO) plays a key role in 
      the regulation of apoptosis, but its role in Fas-induced cell death and the 
      underlying mechanism are largely unknown. Here we show that stimulation of the 
      Fas receptor by its ligand (FasL) results in rapid generation of NO and 
      concomitant decrease in cellular FLICE inhibitory protein (FLIP) expression 
      without significant effect on Fas and Fas-associated death domain (FADD) adapter 
      protein levels. FLIP down-regulation as well as caspase-8 activation and 
      apoptosis induced by FasL were all inhibited by the NO-liberating agent sodium 
      nitroprusside and dipropylenetriamine NONOate, whereas the NO synthase inhibitor 
      aminoguanidine and NO scavenger 
      2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO) had 
      opposite effects, indicating an anti-apoptotic role of NO in the Fas signaling 
      process. FasL-induced down-regulation of FLIP is mediated by a 
      ubiquitin-proteasome pathway that is negatively regulated by NO. S-nitrosylation 
      of FLIP is an important mechanism rendering FLIP resistant to ubiquitination and 
      proteasomal degradation by FasL. Deletion analysis shows that the caspase-like 
      domain of FLIP is a key target for S-nitrosylation by NO, and mutations of its 
      cysteine 254 and cysteine 259 residues completely inhibit S-nitrosylation, 
      leading to increased ubiquitination and proteasomal degradation of FLIP. These 
      findings indicate a novel pathway for NO regulation of FLIP that provides a key 
      mechanism for apoptosis regulation and a potential new target for intervention in 
      death receptor-associated diseases.
FAU - Chanvorachote, Pithi
AU  - Chanvorachote P
AD  - Department of Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, West 
      Virginia University, Morgantown, West Virginia 26506, USA.
FAU - Nimmannit, Ubonthip
AU  - Nimmannit U
FAU - Wang, Liying
AU  - Wang L
FAU - Stehlik, Christian
AU  - Stehlik C
FAU - Lu, Bin
AU  - Lu B
FAU - Azad, Neelam
AU  - Azad N
FAU - Rojanasakul, Yon
AU  - Rojanasakul Y
LA  - eng
GR  - HL071545/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20051024
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Ubiquitin)
RN  - 0 (fas Receptor)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 3.4.22.- (CASP8 protein, human)
RN  - EC 3.4.22.- (Caspase 8)
RN  - EC 3.4.22.- (Caspases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Apoptosis/*physiology
MH  - Blotting, Western
MH  - Caspase 8
MH  - Caspases/*metabolism
MH  - Cell Line
MH  - Enzyme Activation
MH  - Humans
MH  - Hydrolysis
MH  - Immunoprecipitation
MH  - Nitric Oxide/*physiology
MH  - Proteasome Endopeptidase Complex/*metabolism
MH  - Ubiquitin/*metabolism
MH  - fas Receptor/*physiology
EDAT- 2005/10/26 09:00
MHDA- 2006/04/06 09:00
CRDT- 2005/10/26 09:00
PHST- 2005/10/26 09:00 [pubmed]
PHST- 2006/04/06 09:00 [medline]
PHST- 2005/10/26 09:00 [entrez]
AID - S0021-9258(19)48039-3 [pii]
AID - 10.1074/jbc.M510080200 [doi]
PST - ppublish
SO  - J Biol Chem. 2005 Dec 23;280(51):42044-50. doi: 10.1074/jbc.M510080200. Epub 2005 
      Oct 24.