Gene/Protein
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Drug
Enzyme
Compound
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Gene/Protein
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Target Concepts:
Gene/Protein
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Query: EC:2.7.11.25 (
MEKK1
)
1,856
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The antioxidant protein
peroxiredoxin
(
Prx
) I is a
thioredoxin peroxidase
that is involved in the regulation of proliferation and differentiation of mammalian cells. Here, it is shown that
Prx
I gene expression was induced transcriptionally by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in cultured rat liver tissue macrophages and RAW264.7 monocytic cells. TPA-dependent induction of
Prx
I gene expression was mediated by two proximal activator protein-1 sites of the rat
Prx
I promoter region that were nuclear targets of c-Jun as determined by transfection studies with luciferase reporter gene constructs and electrophoretic mobility shift assays. The transcription factor Nrf2, however, was not involved in the regulation of
Prx
I promoter activity.
Prx
I gene induction by TPA was decreased by protein kinase C inhibitors and overexpressed dominant negative forms of Ras and
MEKK1
, but not Raf-1. The p38 MAPK inhibitor SB202190 and overexpression of dominant negative mutants of MAPK kinase 4 (MKK4), MKK6, and p38 inhibited the TPA-dependent induction of
Prx
I gene transcription. In contrast, inhibitors of the JNK, SP600125, and the NF-kappaB signaling pathway, caffeic acid phenethyl ester, respectively, as well as overexpressed dominant negative MKK7 and IkappaB, had no effect on the up-regulation of
Prx
I reporter gene activity by TPA. Cotransfection of wild-type p38alpha and p38beta, but not that of p38gamma and p38delta, increased
Prx
I promoter activity. The data indicate that a protein kinase C, Ras,
MEKK1
, p38 MAPK signaling pathway plays a major role for the transcriptional up-regulation of
Prx
I gene expression.
...
PMID:Phorbol ester-dependent activation of peroxiredoxin I gene expression via a protein kinase C, Ras, p38 mitogen-activated protein kinase signaling pathway. 1296 Jan 65
The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in the cellular response to various stresses and its deregulation accompanies pathological conditions such as cancer and chronic inflammation. Hydrogen peroxide (H
2
O
2
) is a well-established activator of the p38 MAPK signaling pathway. However, the mechanisms of H
2
O
2
-induced p38 activation are not yet fully understood. In Drosophila cells, we find that H
2
O
2
-induced activation of p38 depends on the MAPK kinase kinase (
MAP3K
) Mekk1. In line with the emerging role of peroxiredoxins as H
2
O
2
sensors and signal transmitters we observe an H
2
O
2
-dependent interaction between Mekk1 and the cytosolic
peroxiredoxin
of Drosophila, Jafrac1. In human cells, MEKK4 (the homologue of Mekk1) and
peroxiredoxin
-2 (Prx2) interact in a similar manner, suggesting an evolutionarily conserved mechanism. In both organisms, H
2
O
2
induces transient disulfide-linked conjugates between the
MAP3K
and a typical 2-Cys
peroxiredoxin
. We propose that these conjugates represent the relaying of oxidative equivalents from H
2
O
2
to the
MAP3K
and that the oxidation of Mekk1/MEKK4 leads to the downstream activation of p38 MAPK. Indeed, the depletion of cytosolic 2-Cys peroxiredoxins in human cells diminished H
2
O
2
-induced activation of p38 MAPK.
...
PMID:A role for peroxiredoxins in H
2
O
2
- and MEKK-dependent activation of the p38 signaling pathway. 3162 69
