Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade
Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade
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DOI：
10.1128/mcb.20.12.4265-4274.2000
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发表时间：
2000-06-01
影响因子：
5.3
通讯作者：
Clark, AR
中科院分区：
文献类型：
--
作者：
Lasa, M;Mahtani, KR;Clark, AR
采用四环素调控的报告系统研究丝裂原活化蛋白激酶（MAPK）p38信号级联对环氧化酶2（考克斯-2）mRNA稳定性的调控。通过插入2，500个核苷酸的考克斯-2 3'非翻译区（3' UTR），使稳定的β-珠蛋白mRNA变得不稳定。嵌合体转录物通过MAPK激酶6（p38的激活剂）的组成型活性形式稳定。这种稳定性被阻断SB 203580，p38的抑制剂，并通过两种不同的显性负性形式的MAPK激活的蛋白激酶2（MAPKAPK-2），激酶位于p38的下游。组成型活性MAPKAPK-2也能够稳定嵌合β-珠蛋白-考克斯-2转录物。MAPKAPK-2底物hsp 27可能参与稳定，因为β-珠蛋白-考克斯-2转录物被hsp 27的磷酸化模拟突变形式部分稳定。考克斯-2 3'非翻译区的一个短片段（123个核苷酸）对于通过p38级联调节mRNA稳定性是必要的和足够的，并且与免疫学上与富含AU的元件/聚（U）结合因子1相关的HeLa蛋白相互作用。
A tetracycline-regulated reporter system was used to investigate the regulation of cyclooxygenase 2 (Cox-2) mRNA stability by the mitogen-activated protein kinase (MAPK) p38 signaling cascade. The stable beta-globin mRNA was rendered unstable by insertion of the 2,500-nucleotide Cox-2 3' untranslated region (3' UTR). The chimeric transcript was stabilized by a constitutively active form of MAPK kinase 6, an activator of p38. This stabilization was blocked by SB203580, an inhibitor of p38, and by two different dominant negative forms of MAPK-activated protein kinase 2 (MAPKAPK-2), a kinase lying downstream of p38. Constitutively active MAPKAPK-2 was also able to stabilize chimeric beta-globin-Cox-2 transcripts, The MAPKAPK-2 substrate hsp27 may be involved in stabilization, as beta-globin-Cox-2 transcripts were partially stabilized by phosphomimetic mutant forms of hsp27. A short (123-nucleotide) fragment of the Cox-2 3' UTR was necessary and sufficient for the regulation of mRNA stability by the p38 cascade and interacted with a HeLa protein immunologically related to AU-rich element/poly(U) binding factor 1.