Post-transcriptional control of cyclooxygenase-2 gene expression -: The role of the 3′-untranslated region

被引:310
作者
Dixon, DA
Kaplan, CD
McIntyre, TM
Zimmerman, GA
Prescott, SM
机构
[1] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA
[2] Univ Utah, Eccles Program Human Mol Biol & Genet, Dept Oncol Sci, Salt Lake City, UT 84112 USA
关键词
D O I
10.1074/jbc.275.16.11750
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The cyclooxygenase (COX)-2 enzyme is responsible for increased prostaglandin formation in inflammatory states and is the major target of nonsteroidal anti-inflammatory drugs. Normally COX-2 expression is tightly regulated, however, constitutive overexpression plays a hey role in colon carcinogenesis. To understand the mechanisms controlling COX-2 expression, we examined the ability of the 3'-untranslated region of the COX-2 mRNA to regulate post-transcriptional events. When fused to a reporter gene, the 3'-untranslated region mediated rapid mRNA decay (t(1/2) = 30 min), which was comparable to endogenous COX-2 mRNA turnover in serum-induced fibroblasts treated with actinomycin D or dexamethasone. Deletion analysis demonstrated that a conserved 116-nucleotide AU-rich sequence element (ARE) mediated mRNA degradation. In transiently transfected cells, this region inhibited protein synthesis approximately 3-fold. However, this inhibition did not occur through changes in mRNA stability since mRNA half-life and steady-state mRNA levels were unchanged. RNA mobility shift assays demonstrated a complex of cytoplasmic proteins that bound specifically to the ARE, and UV cross-linking studies identified proteins ranging from 90 to 35 kDa. Fractionation of the cytosol showed differential association of ARE-binding proteins to polysomes and S130 fractions. We propose that these factors influence expression at a post-transcriptional step and, if dysregulated, may increase COX-2 protein as detected in colon cancer.
引用
收藏
页码:11750 / 11757
页数:8
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