Cross-talk between the estrogen receptor-, protein kinase A-, and mitogen-activated protein kinase-mediated signaling pathways in the regulation of lactotroph proliferation in primary culture
Cross-talk between the estrogen receptor-, protein kinase A-, and mitogen-activated protein kinase-mediated signaling pathways in the regulation of lactotroph proliferation in primary culture
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DOI：
10.1016/j.jsbmb.2003.11.003
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发表时间：
2004-02
期刊：
影响因子：
--
通讯作者：
K. Yamakawa;J. Arita
中科院分区：
文献类型：
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作者：
K. Yamakawa;J. Arita
利用药理学手段，我们研究了雌激素受体(ER)-、蛋白激酶A (PKA)-和丝裂原活化蛋白激酶(MAPK)-介导的途径在原代培养中调节嗜乳细胞增殖中的功能相互作用。用PKA抑制剂H89或KT5720（一种有效的福斯克林诱导的增殖抑制剂）处理乳养菌28小时，可抑制胰岛素和雌二醇诱导的增殖。PD98059或U0126抑制MAPK活性不仅抑制胰岛素诱导的增殖，而且抑制forskolin和雌二醇诱导的增殖。然而，抗雌激素4-羟基他莫昔芬和ICI182780治疗28h后，并不能抑制雌二醇诱导的乳营养细胞增殖，反而增强了其增殖。将抗雌激素治疗时间从28小时延长至88小时，可以有效地拮抗雌二醇诱导的细胞增殖，这种长期治疗还可以抑制胰岛素和福斯克林诱导的细胞增殖。用孕酮拮抗剂或蛋白激酶C抑制剂治疗后，这些丝裂原诱导的增殖没有减少。这些结果表明，ER-、PKA-和mapk介导的信号通路在乳营养细胞增殖的调节中发生串扰，抗雌激素以时间依赖性的方式刺激和抑制雌二醇诱导的增殖。
Using pharmacological means we investigated the functional interactions between the estrogen receptor (ER)-, protein kinase A (PKA)-, and mitogen-activating protein kinase (MAPK)-mediated pathways in the regulation of lactotroph proliferation in primary culture. Treatment of lactotrophs for 28h with the PKA inhibitor H89 or KT5720, an effective inhibitor of forskolin-induced proliferation, inhibited both insulin- and estradiol-induced proliferation. Inhibition of the MAPK activity by PD98059 or U0126 suppressed not only insulin-induced proliferation but also forskolin- and estradiol-induced proliferation. However, treatment for 28h with the antiestrogens 4-hydroxy tamoxifen and ICI182780 failed to antagonize estradiol-induced lactotroph proliferation but instead enhanced it. Prolonging the antiestrogen treatment time from 28 to 88h was effective in antagonizing estradiol-induced proliferation with this long-term treatment also inhibiting insulin- and forskolin-induced proliferation. There was no decrease in these mitogen-induced proliferations following treatment with a progesterone antagonist or protein kinase C inhibitor. These results suggest that cross-talk occurs between the ER-, PKA-, and MAPK-mediated signaling pathways in the regulation of lactotroph proliferation, and that antiestrogens stimulate and inhibit estradiol-induced proliferation in a time-dependent manner.