Translational regulation of cyclin D1 by 15-deoxy-delta(12,14)-prostaglandin J(2).
Translational regulation of cyclin D1 by 15-deoxy-delta(12,14)-prostaglandin J(2).
复制标题
DOI：
--
复制
发表时间：
2002-09
期刊：
影响因子：
--
通讯作者：
P. A. Campo;Sonali Das;C. Hsiang;T. Bui;C. E. Samuel;D. Straus
中科院分区：
文献类型：
--
作者：
P. A. Campo;Sonali Das;C. Hsiang;T. Bui;C. E. Samuel;D. Straus
D-组细胞周期蛋白在细胞周期的G（1）期的进展中起关键作用。用环戊烯酮前列腺素15-脱氧-Delta（12，14）-PGJ（2）（15 d-PGJ（2））处理MCF-7乳腺癌细胞导致细胞周期蛋白D1蛋白表达的快速下调和细胞周期G（0）/G（1）期的生长停滞。15 d-PGJ（2）也下调细胞周期蛋白D1 mRNA的表达;然而，相对于对细胞周期蛋白D1蛋白水平的影响，这种作用是延迟的，这表明细胞周期蛋白D1的调节至少部分发生在翻译或蛋白质周转水平。用15 d-PGJ（2）处理MCF-7细胞，导致蛋白质合成起始因子真核起始因子2 α（eIF-2 α）磷酸化水平迅速增加，细胞周期蛋白D1 mRNA从多聚体相关mRNA部分转移到游离mRNA部分，表明15 d-PGJ（2）抑制细胞周期蛋白D1 mRNA翻译的起始。细胞周期蛋白D1蛋白质积累的选择性快速减少是由其快速周转（t（1/2）= 34分钟）后，抑制细胞周期蛋白D1蛋白质的合成。在用15 d-PGJ处理的细胞中，细胞周期蛋白D1蛋白的半衰期没有显著改变（2）。用15 d-PGJ（2）处理细胞导致热休克蛋白70（HSP 70）基因表达的强烈诱导，表明15 d-PGJ（2）可能激活蛋白激酶R（PKR），这是一种先前显示对诱导应激的药物有反应的eIF-2 α激酶。15 d-PGJ（2）在野生型小鼠胚胎成纤维细胞衍生的细胞系中强烈刺激eIF-2 α磷酸化并下调细胞周期蛋白D1表达，但在PKR缺失细胞中的作用减弱，这提供了PKR参与介导15 d-PGJ（2）对eIF-2 α磷酸化和细胞周期蛋白D1表达的作用的证据。总之，用15 d-PGJ处理MCF-7细胞（2）导致eIF-2 α磷酸化增加和细胞周期蛋白D1 mRNA翻译起始抑制。在以后的时间点，细胞周期蛋白D1 mRNA表达的抑制也可能有助于细胞周期蛋白D1蛋白的减少。
The D-group cyclins play a key role in the progression of cells through the G(1) phase of the cell cycle. Treatment of MCF-7 breast cancer cells with the cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) results in rapid down-regulation of cyclin D1 protein expression and growth arrest in the G(0)/G(1) phase of the cell cycle. 15d-PGJ(2) also down-regulates the expression of cyclin D1 mRNA; however, this effect is delayed relative to the effect on cyclin D1 protein levels, suggesting that the regulation of cyclin D1 occurs at least partly at the level of translation or protein turnover. Treatment of MCF-7 cells with 15d-PGJ(2) leads to a rapid increase in the phosphorylation of protein synthesis initiation factor eukaryotic initiation factor 2alpha (eIF-2alpha) and a shift of cyclin D1 mRNA from the polysome-associated to free mRNA fraction, indicating that 15d-PGJ(2) inhibits the initiation of cyclin D1 mRNA translation. The selective rapid decrease in cyclin D1 protein accumulation is facilitated by its rapid turnover (t(1/2) = 34 min) after inhibition of cyclin D1 protein synthesis. The half-life of cyclin D1 protein is not significantly altered in cells treated with 15d-PGJ(2). Treatment of cells with 15d-PGJ(2) results in strong induction of heat shock protein 70 (HSP70) gene expression, suggesting that 15d-PGJ(2) might activate protein kinase R (PKR), an eIF-2alpha kinase shown previously to be responsive to agents that induce stress. 15d-PGJ(2) strongly stimulates eIF-2alpha phosphorylation and down-regulates cyclin D1 expression in a cell line derived from wild-type mouse embryo fibroblasts but has an attenuated effect in PKR-null cells, providing evidence that PKR is involved in mediating the effect of 15d-PGJ(2) on eIF-2alpha phosphorylation and cyclin D1 expression. In summary, treatment of MCF-7 cells with 15d-PGJ(2) results in increased phosphorylation of eIF-2alpha and inhibition of cyclin D1 mRNA translation initiation. At later time points, repression of cyclin D1 mRNA expression may also contribute to the decrease in cyclin D1 protein.