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:2.7.12.2 (
MEK
)
18,161
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), is used in treatments for transplantation and cancer. Rapamycin causes hypomagnesemia, although precisely how has not been examined. Here, we investigated the effect of rapamycin on the expression of
transient receptor potential melastatin 6
(
TRPM6
), a Mg2+ channel. Rapamycin and LY-294002, an inhibitor of phosphatidilinositol-3 kinase (PI3K) located upstream of mTOR, inhibited epidermal growth factor (EGF)-induced expression of the
TRPM6
protein without affecting TRPM7 expression in rat renal NRK-52E epithelial cells. Both rapamycin and LY-294002 decreased EGF-induced Mg2+ influx. U0126, a
MEK
inhibitor, inhibited EGF-induced increases in c-Fos, p-ERK, and
TRPM6
levels. In contrast, neither rapamycin nor LY-294002 inhibited EGF-induced increases in p-ERK and c-Fos levels. EGF increased p-Akt level, an effect inhibited by LY-294002 and 1L-6-hydroxymethyl-chiro-inositol2-[(R)-2-O-methyl-3-O-octadecylcarbonate] (Akt inhibitor). Akt inhibitor decreased
TRPM6
level similar to rapamycin and LY-294002. These results suggest that a PI3K/Akt/mTOR pathway is involved in the regulation of
TRPM6
expression. Rapamycin inhibited the EGF-induced increase in
TRPM6
mRNA but did not inhibit human
TRPM6
promoter activity. In the presence of actinomycin D, a transcriptional inhibitor, rapamycin accelerated the decrease in
TRPM6
mRNA. Rapamycin decreased the expression and activity of a luciferase linked with the 3'-untranslated region of human
TRPM6
mRNA. These results suggest that
TRPM6
expression is up-regulated by a PI3K/Akt/mTOR pathway and rapamycin reduces
TRPM6
mRNA stability, resulting in a decrease in the reabsorption of Mg2+.
...
PMID:Decrease in transient receptor potential melastatin 6 mRNA stability caused by rapamycin in renal tubular epithelial cells. 2107 57
A chronic magnesium deficiency may be one of the causes of lifestyle-related diseases such as hypertension and diabetes. Serum Mg
2+
concentration is strictly controlled by the reabsorption pathway in the renal tubules, but little is known about how Mg
2+
reabsorption is upregulated. We searched for food compounds which can increase the expression levels of Mg
2+
transport carriers including
transient receptor potential melastatin 6
(
TRPM6
) channel and cyclin M2 (CNNM2). Sodium citrate (SC) increased the mRNA levels of
TRPM6
and CNNM2 in renal tubular epithelial NRK-52E cells. The SC-induced elevation of
TRPM6
was inhibited by U0126, a
mitogen-activated protein kinase kinase
(
MEK
) inhibitor, but the CNNM2 was not. SC increased the levels of p-ERK1/2 and p-c-Fos, which were inhibited by U0126. SC induced alkalization of culture medium. Both SC and alkalization enhanced Mg
2+
influx, which was inhibited by U0126 and introduction of
TRPM6
siRNA. The reporter activity of
TRPM6
was increased by SC and alkalization, which was suppressed by mutation in an AP-1-binding site. The SC-induced elevation of p-ERK1/2 and p-EGFR was inhibited by diphenylene iodonium, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, and erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. SC did not change the level of acetyl histone H3, but increased the association of c-Fos with the promoter region of
TRPM6
. These results suggest that SC increases
TRPM6
expression and Mg
2+
influx mediated by the activation of NADPH oxidase and an EGFR/ERK/c-Fos pathway in the renal tubules.
...
PMID:Sodium Citrate Increases Expression and Flux of Mg
2+
Transport Carriers Mediated by Activation of MEK/ERK/c-Fos Pathway in Renal Tubular Epithelial Cells. 3024 94
