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Target Concepts:
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Query: EC:3.4.24.35 (
matrix metalloproteinase 9
)
2,207
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Dysregulation of extracellular matrix turnover is an important feature of many inflammatory processes. Rat renal mesangial cells express high levels of
matrix metalloproteinase 9
(
MMP-9
) in response to inflammatory cytokines such as interleukin-1 beta. We demonstrate that NO does strongly destabilize
MMP-9
mRNA, since different luciferase reporter gene constructs containing the
MMP-9
3' untranslated region (UTR) displayed significant reduced luciferase activity in response to the presence of NO. Moreover, by use of an in vitro degradation assay we found that the cytoplasmic fractions of NO-treated cells contained a higher capacity to degrade
MMP-9
transcripts than those obtained from control cells. An RNA electrophoretic mobility shift assay demonstrated that three of four putative AU-rich elements present in the 3' UTR of
MMP-9
were constitutively occupied by the mRNA-stabilizing factor
HuR
and that the RNA binding was strongly attenuated by the presence of NO. The addition of recombinant glutathione transferase-
HuR
prevented the rapid decay of
MMP-9
mRNA, whereas the addition of a neutralizing anti-
HuR
antibody caused an acceleration of
MMP-9
mRNA degradation. Furthermore, the expression of
HuR
mRNA and protein was significantly reduced by exogenously and endogenously produced NO. These inhibitory effects were mimicked by the cGMP analog 8-bromo-cGMP and reversed by LY-83583, an inhibitor of soluble guanylyl cyclase. These results demonstrate that NO acts in a cGMP-dependent mechanism to inhibit the expression level of
HuR
, thereby reducing the stability of
MMP-9
mRNA.
...
PMID:Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA-stabilizing factor HuR. 1283 76
Renal mesangial cells express high levels of
matrix metalloproteinase 9
(
MMP-9
) in response to inflammatory cytokines such as interleukin (IL)-1 beta. We demonstrate here that the stable ATP analog adenosine 5'-O-(thiotriphosphate) (ATP gamma S) potently amplifies the cytokine-induced gelatinolytic content of mesangial cells mainly by an increase in the
MMP-9
steady-state mRNA level. A Luciferase reporter gene containing 1.3 kb of the
MMP-9
5'-promoter region showed weak responses to ATP gamma S but conferred a strong ATP-dependent increase in Luciferase activity when under the additional control of the 3'-untranslated region of
MMP-9
. By in vitro degradation assay and actinomycin D experiments we found that ATP gamma S potently delayed the decay of
MMP-9
mRNA. Gel-shift and supershift assays demonstrated that three AU-rich elements (AREs) present in the 3'-untranslated region of
MMP-9
are constitutively bound by complexes containing the mRNA stabilizing factor
HuR
. The RNA binding of these complexes was markedly increased by ATP gamma S. Mutation of each ARE element strongly impaired the RNA binding of the
HuR
containing complexes. Reporter gene assays revealed that mutation of one ARE did not affect the stimulatory effects by ATP gamma S, but mutation of all three ARE motifs caused a loss of ATP-dependent increase in luciferase activity without affecting IL-1 beta-inducibility. By confocal microscopy we demonstrate that ATP gamma S increased the nucleo cytoplasmic shuttling of
HuR
and caused an increase in the cytosolic
HuR
level as shown by cell fractionation experiments. Together, our results indicate that the amplification of
MMP-9
expression by extracellular ATP is triggered through mechanisms that likely involve a
HuR
-dependent rise in
MMP-9
mRNA stability.
...
PMID:ATP potentiates interleukin-1 beta-induced MMP-9 expression in mesangial cells via recruitment of the ELAV protein HuR. 1452 3
