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: UNIPROT:P51812 (
mitogen-activated protein
)
10,636
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
SAF-1
, a zinc finger transcription factor, is activated by a number of inflammatory agents, including interleukin-1 (IL-1) and IL-6. It is involved in the cytokine-mediated transcriptional induction of serum amyloid A, an acute-phase plasma protein that is associated with the pathogenesis of reactive amyloidosis, rheumatoid arthritis, and atherosclerosis. Here, we show that the
mitogen-activated protein
(
MAP
) kinase signaling pathway regulates cytokine-mediated induction of the DNA-binding activity and transactivation potential of
SAF-1
. Phosphorylation of endogenous
SAF-1
in response to IL-1 and IL-6 was markedly inhibited by the addition of MAP kinase inhibitors. Consistent with this finding, we show that a consensus MAP kinase phosphorylation site, PPTP, within
SAF-1
could be phosphorylated by MAP kinase in vitro. To analyze the contribution of MAP kinase in the activation of
SAF-1
, we prepared two independent mutant proteins in which the threonine residue of the PPTP motif was altered to either valine or alanine. These mutant proteins lost the ability to be phosphorylated by MAP kinase both in vivo and in vitro and exhibited a significantly reduced ability to promote expression of the
SAF-1
-regulated promoter. While the DNA-binding activity of wild-type
SAF-1
protein was markedly increased upon phosphorylation with MAP kinase, no such increase could be detected with the mutant
SAF-1
proteins. Further analysis with the GAL-4 reporter system showed that mutation of the MAP kinase phosphorylation site considerably lowers the transactivation potential of
SAF-1
. Together, these results show that activation of
SAF-1
in response to IL-1 and -6 is mediated via MAP kinase-regulated phosphorylation.
...
PMID:Cytokine-responsive induction of SAF-1 activity is mediated by a mitogen-activated protein kinase signaling pathway. 1180 95
