Induction of cyclooxygenase-2 by activated Ha-ras oncogene in rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway

被引:171
作者
Sheng, HM
Williams, CS
Shao, JY
Liang, P
DuBois, RN
Beauchamp, RD
机构
[1] Vanderbilt Univ, Ctr Med, Ctr Canc, Dept Surg, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Ctr Med, Ctr Canc, Dept Med, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Ctr Med, Ctr Canc, Dept Cell Biol, Nashville, TN 37232 USA
关键词
D O I
10.1074/jbc.273.34.22120
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
Elevated cyclooxygenase-2 (COX-2) expression and activity have been observed in several different transformed cell types that express mutated ras genes. To investigate the mechanism of increased COX-2 expression following Ras-mediated transformation, Rat-1:iRas cell line was transfected with an Ha-Ras(Val-12) cDNA expressions vector that is under the transcriptional control of the lac operon and is inducible with isopropyl-1-thio-beta-D-galactopyranoside (IPTG). IPTG treatment caused parallel increases in the levels of Ha-Ras and COX-2 proteins in Rat-1:iRas cells. The increased expression of COX-2 was accompanied by increased prostaglandin E-2 production. Selective inhibition of COX-2 activity suppressed the production of prostaglandin E-2 by >90% but did not alter the progress of the morphological transformation. The Bevel of COX-2 mRNA was up-regulated by activated Ha-Ras. Induction of Ras increased the transcription of COX-2 by 44.3 +/- 10.1% and increased the half-life of COX-2 mRNA by similar to 3.5-fold. A specific mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) inhibitor (PD 98059) caused a delay in both the activation of ERK1/2 and the induction of COX-2 in IPTG-induced Rat-1:iRas cells. Inhibition of ERK activity by PD 98059 also suppressed the induction of COX-2 by epidermal growth factor in intestinal epithelial cells and significantly reduced the expression of COX-2 in Ha-Ras-transformed rat intestinal epithelial cells. ERK activity appears to be required for induction of COX-2 by Ras.
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页码:22120 / 22127
页数:8
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