Vitamin E Succinate Induces NAG-1 Expression In A P38 Kinase

Wilfrid

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Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism.
Shim M, Eling TE.
Eicosanoids Biochemistry Section, Laboratory of Molecular Carcinogenesis,
National Institute of Environmental Health Sciences, NIH, 111 T.W. Alexander
Drive, Research Triangle Park, NC 27709, USA.


"NAG-1 (nonsteroidal anti-inflammatory drug-activated gene), a member of the
transforming growth factor-beta superfamily, is involved in many cellular
processes, such as inflammation, apoptosis/survival, and tumorigenesis.
Vitamin E
succinate (VES) is the succinate derivative of alpha-tocopherol and has
antitumorigenic activity in a variety of cell culture and animal models. In the
current study, the regulation and role of NAG-1 expression in PC-3 human prostate
carcinoma cells by VES was examined.
VES treatment induced growth arrest and
apoptosis as well as an increase in NAG-1 protein and mRNA levels in a time- and 
concentration-dependent manner.
VES treatment induced nuclear translocation and
activation of p38 kinase. Pretreatment with p38 kinase inhibitor blocked the
VES-induced increase in NAG-1 protein and mRNA levels, whereas an inhibition of
protein kinase C, Akt, c-Jun NH(2)-terminal kinase, or MEK activity had no effect
on VES-induced NAG-1 levels. Forced expression of constitutively active MKK6, an 
upstream kinase for p38, induced an increase in NAG-1 promoter activity, whereas 
p38 kinase inhibitor blocked MKK6-induced increase in NAG-1 promoter activity.
VES treatment resulted in >3-fold increase in the half-life of NAG-1 mRNA in a
p38 kinase-dependent manner and transient transfection experiment showed that VES
stabilizes NAG-1 mRNA through AU-rich elements in 3'-untranslated region of NAG-1
mRNA. The inhibition of NAG-1 expression by small interfering RNA significantly
blocked VES-induced poly(ADP-ribose) polymerase cleavage, suggesting that NAG-1
may play an important role in VES-induced apoptosis
. These results indicate that 
VES-induced expression of NAG-1 mRNA/protein is regulated by
transcriptional/post-transcriptional mechanism in a p38 kinase-dependent manner
and NAG-1 can be chemopreventive/therapeutic target in prostate cancer."
 

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