Altered MAP kinase (ERK1,2) regulation in primary cultures of mammary tumor cells: elevated basal activity and sustained response to EGF.
Altered MAP kinase (ERK1,2) regulation in primary cultures of mammary tumor cells: elevated basal activity and sustained response to EGF.
复制标题
乳腺肿瘤细胞原代培养物中 MAP 激酶 (ERK1,2) 调节的改变：基础活性升高和对 EGF 的持续反应。
DOI：
10.1093/carcin/20.7.1201
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发表时间：
1999
期刊：
影响因子：
4.7
通讯作者：
Imagawa,W
中科院分区：
文献类型：
--
作者：
Xing,C;Imagawa,W
在乳腺癌组织中观察到总MAP激酶活性和表达的升高。然而，这些激酶活性变化和生长因子调节的机制还没有得到很好的表征。在这些研究中，有效的乳腺有丝分裂原，表皮生长因子（EGF），对有丝分裂原活化的蛋白激酶，ERK 1和ERK 2（细胞外调节蛋白激酶1和2，分别）的激活的影响，进行了比较，在正常小鼠乳腺上皮细胞的原代培养物，并在乳腺癌反应性小鼠乳腺肿瘤。在正常上皮细胞中，EGF刺激ERK活性在4分钟后迅速下降，而持续（1小时）的ERK活性升高，观察到在肿瘤细胞中的早期上升。ERK活性在两种细胞类型中的时间过程与EGF受体的磷酸化状态相一致，这表明EGF受体磷酸化或EGF受体周转的调节改变产生了增强的ERK对肿瘤细胞中EGF的反应。MEK抑制剂PD 098059以平行的剂量依赖性方式抑制EGF刺激的增殖和ERK活性，表明ERK活化至少允许对EGF的增殖反应。此外，肿瘤细胞表现出4倍的基础（或配体非依赖性）活性高于正常细胞，而不增加总酶水平，并通过EGF优先激活ERK 1。这些EGF依赖性和非依赖性的变化，ERK的调节在乳腺癌反应性乳腺肿瘤强调了多种改变，这条途径的调节可能在乳腺肿瘤的发生中发挥作用。
An elevation in total MAP kinase activity and expression has been observed in breast cancer tissue. However, the mechanisms underlying these changes in kinase activity and regulation by growth factors are not well characterized. In these studies, the effect of the potent mammary mitogen, epidermal growth factor (EGF), on the activation of the mitogen-activated protein kinases, ERK1 and ERK2 (extracellular regulated protein kinases 1 and 2, respectively), was compared in primary cultures of normal mouse mammary epithelial cells and in a hormone-responsive mouse mammary tumor. In normal epithelium, EGF stimulated an early rise in ERK activity at 4 min followed by a rapid decline, whereas a sustained (1 h) elevation of ERK activity was observed in the tumor cells. The time course of ERK activity in both cell types coincided with the phosphorylation state of the EGF receptor, suggesting that altered regulation of EGF receptor phosphorylation or EGF receptor turnover produces an enhanced ERK response to EGF in tumor cells. The MEK inhibitor, PD 098059 inhibited EGF-stimulated proliferation and ERK activity in a parallel, dose-dependent manner showing that ERK activation is at least permissive for the proliferative response to EGF. In addition, tumor cells showed a 4-fold elevation in basal (or ligand-independent) activity over normal cells without an increase in total enzyme level, and a preferential activation of ERK1 by EGF. These EGF-dependent and -independent changes in ERK regulation in the hormone-responsive mammary tumor underscore how multiple alterations in the regulation of this pathway may play a role in mammary tumorigenesis.