Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.6.3.1 (
NADPH oxidase
)
11,281
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The human
olfactomedin 4
gene (
OLFM4
, also known as
hGC-1
,
GW112
) is thought to be a useful marker for early myeloid development. To understand the molecular mechanisms underlying granulocyte colony-stimulating factor (G-CSF)-stimulated
OLFM4
expression, we characterized the promoter region of
OLFM4
. The 35-bp region (-101 to -66) of the proximal promoter regulated reporter gene expression, and mutation of the nuclear factor (NF)-kappaB binding site within the promoter abolished the binding of the transcription factor and the ability to regulate
OLFM4
expression. G-CSF increased reactive oxygen species (ROS) production in human CD34(+) cells, which was abrogated by inhibition of phosphatidylinositol 3-kinase (PI3K) or
NADPH oxidase
. Phosphorylation of ERK1/2 mitogen-activated protein kinase (MAPK) induced by G-CSF inhibited by the antioxidant N-acetyl-L-cysteine (NAC), ERK1/2 inhibitor PD98059, or U0126. However, phosphorylation of signal transducer and activator of transcription (STAT)3 was only partially inhibited by NAC, but not by PD98059 or U0126. Inhibition of the ERK pathway remarkably decreased
OLFM4
expression and this inhibition required NF-kappaB transcription factor. Inhibition of ROS or the ERK pathway remarkably decreased G-CSF-induced
OLFM4
expression. Our results suggest that G-CSF-induced expression of
OLFM4
is regulated by the transcription factor NF-kappaB, and that this induction is mediated by the ERK1/2 MAPK signaling pathway through PI3K-driven ROS production.
...
PMID:The regulation of OLFM4 expression in myeloid precursor cells relies on NF-kappaB transcription factor. 1876 68
Neutrophils increase production of reactive oxygen species, including superoxide, hydrogen peroxide (H
2
O
2
), and hydroxyl radical, to destroy invading microorganisms under pathological conditions. Conversely, oxidative stress conditions, such as the presence of H
2
O
2
, induce neutrophil apoptosis, which helps to remove neutrophils after inflammation. However, the detailed molecular mechanisms that are involved in the latter process have not been elucidated. In this study, we investigated the potential role of
olfactomedin 4
(Olfm4) in H
2
O
2
-induced superoxide production and apoptosis in mouse neutrophils. We have demonstrated that Olfm4 is not required for maximal-dosage PMA- and Escherichia coli bacteria-induced superoxide production, but Olfm4 contributes to suboptimal-dosage PMA- and H
2
O
2
-induced superoxide production. Using an
NADPH oxidase
inhibitor and gp91phox-deficient mouse neutrophils, we found that NAPDH oxidase was required for PMA-stimulated superoxide production and that Olfm4 mediated H
2
O
2
-induced superoxide production through
NADPH oxidase
, in mouse neutrophils. We have shown that neutrophils from Olfm4-deficient mice exhibited reduced H
2
O
2
-induced apoptosis compared with neutrophils from wild-type mice. We also demonstrated that neutrophils from Olfm4-deficient mice exhibited reduced H
2
O
2
-stimulated mitochondrial damage and membrane permeability, and as well as reduced caspase-3 and caspase-9 activity, compared with neutrophils from wild-type mice. Moreover, the cytoplasmic translocation of the proapoptotic mitochondrial proteins Omi/HtrA2 and Smac/DIABLO in response to H
2
O
2
was reduced in neutrophils from Olfm4-deficient mice compared with neutrophils from wild-type mice. Our study demonstrates that Olfm4 contributes to H
2
O
2
-induced
NADPH oxidase
activation and apoptosis in mouse neutrophils. Olfactomedin 4 might prove to be a potential target for future studies on inflammatory neutrophil biology and for inflammatory disease treatment.
...
PMID:Olfactomedin 4 contributes to hydrogen peroxide-induced NADPH oxidase activation and apoptosis in mouse neutrophils. 2994 2
