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DAN A. DIXON, PhD
Dixon
DA. Dysregulated post-transcriptional control of COX-2 gene
expression in cancer. Curr Pharm Des. 2004;10(6):635-46.
Review.
The cyclooxygenase-2 (COX-2) enzyme
catalyzes the rate-limiting step of prostaglandin formation
in pathogenic states. The molecular regulation of COX-2 gene
expression is normally tightly regulated on transcriptional
and post-transcriptional levels. However, loss of function
at either level of COX-2 gene regulation promotes
constitutive COX-2 overexpression which plays a key role in
carcinogenesis, particularly colorectal tumorigenesis.
Current work investigating the regulatory mechanisms of
COX-2 expression has demonstrated post-transcriptional
regulation to play a central role. Rapid COX-2 mRNA decay
and translational inhibition is mediated through a conserved
AU-rich element (ARE) present within the 3'-untranslated
region (3'UTR). The COX-2 ARE exerts its control through
association with ARE RNA-binding proteins. These
trans-acting regulatory factors influence the fate of COX-2
mRNA by controlling mRNA degradation, stabilization, or
translation. Recent evidence demonstrates the functional
significance rapid mRNA decay and translational inhibition
play in controlling COX-2 gene expression and that, if
dysregulated, allow for overexpression of COX-2 and other
associated angiogenic factors detected in neoplasia.
Dixon DA, Balch GC, Kedersha N,
Anderson P, Zimmerman GA, Beauchamp RD, Prescott SM.
Regulation of cyclooxygenase-2 expression by the
translational silencer TIA-1. J Exp Med. 2003 Aug
4;198(3):475-81.
The cyclooxygenase-2 (COX-2) enzyme
catalyzes the rate-limiting step of prostaglandin formation
in inflammatory states, and COX-2 overexpression plays a key
role in carcinogenesis. To understand the mechanisms
regulating COX-2 expression, we examined its
posttranscriptional regulation mediated through the AU-rich
element (ARE) within the COX-2 mRNA 3'-untranslated region
(3'UTR). RNA binding studies, performed to identify
ARE-binding regulatory factors, demonstrated binding of the
translational repressor protein TIA-1 to COX-2 mRNA. The
significance of TIA-1-mediated regulation of COX-2
expression was observed in TIA-1 null fibroblasts that
produced significantly more COX-2 protein than wild-type
fibroblasts. However, TIA-1 deficiency did not alter COX-2
transcription or mRNA turnover. Colon cancer cells
demonstrated to overexpress COX-2 through increased polysome
association with COX-2 mRNA also showed defective TIA-1
binding both in vitro and in vivo. These findings implicate
that TIA-1 functions as a translational silencer of COX-2
expression and support the hypothesis that dysregulated
RNA-binding of TIA-1 promotes COX-2 expression in neoplasia.
Subbaramaiah K, Marmo TP, Dixon DA,
Dannenberg AJ. Regulation of cyclooxgenase-2 mRNA stability
by taxanes: evidence for involvement of p38, MAPKAPK-2, and
HuR. J Biol Chem. 2003 Sep 26;278(39):37637-47.
Taxanes are widely used to treat
malignancies and are known to modulate the transcription of
several genes. We investigated the effects of taxanes (docetaxel
and paclitaxel) on cyclooxygenase-2 (COX-2) transcription
and mRNA stability in human mammary epithelial cells. As
reported previously for paclitaxel, docetaxel stimulated
COX-2 transcription by an AP-1-dependent mechanism.
Treatment with taxanes also enhanced the stability of COX-2
mRNA. To define the mechanism by which taxanes stabilized
COX-2 mRNA, transient transfections were carried out using
luciferase expression constructs containing the COX-2
3'-untranslated region (3'-untranslated region (UTR)). The
stabilizing effects of taxanes were localized to the AU-rich
region of COX-2 3'-UTR. RNA binding studies indicated that
taxanes stimulated the binding of HuR to the AU-rich region
of the COX-2 3'-UTR. Overexpression of antisense HuR
suppressed taxane-mediated induction of COX-2 3'-UTR
activity. We next investigated the signal transduction
pathway responsible for taxane-mediated induction of COX-2.
Taxanes enhanced protein kinase C activity; overexpressing
dominant negative PKC-alpha suppressed taxane-mediated
stimulation of both COX-2 3'-UTR and 5'-promoter activities.
Interestingly, ERK1/2, JNK, and p38 MAPKs were important for
taxane-mediated activation of COX-2 transcription, but only
p38 MAPK appeared to be responsible for the increase in
COX-2 mRNA stability. MAPKAPK-2, a known target of p38 MAPK,
contributed to increased COX-2 mRNA stability following
taxane treatment. SB 202190, a selective p38 MAPK inhibitor,
and dexamethasone suppressed taxane-mediated stimulation of
the COX-2 3'-UTR and binding of HuR. Taken together, these
data indicate that taxanes induce COX-2 by stimulating both
transcription and mRNA stability. To the best of our
knowledge, this is the first evidence that taxanes can
promote stabilization of mRNA in addition to modulating gene
transcription.
Dixon DA. Regulation of COX-2
expression in human cancers. Prog Exp Tumor Res.
2003;37:52-71. Review.
No abstract available.
Sawaoka H, Dixon DA, Oates JA, Boutaud
O. Tristetraprolin binds to the 3'-untranslated region of
cyclooxygenase-2 mRNA. A polyadenylation variant in a cancer
cell line lacks the binding site. J Biol Chem. 2003 Apr
18;278(16):13928-35.
In human colorectal adenocarcinoma cell
lines, we found two major transcripts of cyclooxygenase-2,
the full-length mRNA and a short polyadenylation variant
(2577 kb) lacking the distal segment of the 3'-untranslated
region. Tristetraprolin, an mRNA-binding protein that
promotes message instability, was shown to bind the
cyclooxygenase-2 mRNA in the region of the 3'-untranslated
region between nucleotides 3125 and 3432 and to reduce
levels of the full-length mRNA. During cell growth and
confluence, the expression of tristetraprolin mRNA was
inversely correlated with that of the full-length
cyclooxygenase-2 transcript, and transfection of
tristetraprolin into HCA-7 cells reduced the level of
full-length cyclooxygenase-2 mRNA. However, the truncated
transcript escaped tristetraprolin binding and
downregulation.
Zimmerman GA, Dixon DA, McIntyre TM,
Prescott SM and Weyrich AS. Molecular Mechanisms of
Juxtacrine Signaling in Microvascular Responses and
Inflammation. Molecular Mechanisms of Microvascular
Disorders. eds. Schmid-Schoenbein, G.W., Granger, N.D.
Springer Verlag 2003, pp.203-217.
No abstract available.
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