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Intracellular signal transduction pathways regulating proliferation of anterior pituitary cells

调节垂体前叶细胞增殖的细胞内信号转导通路

基本信息

批准号：
10670060
负责人：
ARITA Jun
金额：
$ 2.11万
依托单位：
Yamanashi Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670060/
关键词：
anterior pituitary gland cell proliferation cyclic AMP MAP kinase CREB 増殖サククリックAMP

项目摘要

We investigated the interaction of two signal transduction pathways of cyclic AMP/protein kinase A (PKA) and MAP kinase cascade which regulate the proliferation of lactotrophs.(1) The MAP kinase inhibitor PD98059 was effective in inhibiting the mitogenic action not only of insulin but also of forskolin that increased intracellular cyclic AMP levels, suggesting the requirement of the MAP kinase cascade for the mitogenic action of cyclic AMP/PKA.(2) The PKA inhibitors H89 and KT5720 were effective in inhibiting the mitogenic action not only of forskolin but also of insulin, suggesting the requirement of cyclic AMP/PKA for the mitogenic action of growth factors such as insulin.(3) Phosphorylated MAP kinase in lactotrophs was immunostained with a selective antibody to estimate the activity of MAP kinase. Although the number of phosphorylated MAP kinase-immunoreactive lactotrophs was altered by dibutyryl cyclic AMP or forskolin, the number of phosphorylated CREB-immunoreactive lactotrophs was increased by forskolin and insulin-like growth factor-1.(4) The p70S6k inhibitor rapamycin inhibited insulin- or forskolin-induced lactotroph proliferation as well as proliferation induced by estradiol, a physiologically important mitogen. Rapamycin inhibited insulin-, but not forskolin-induced proliferation in the presence of the dopamine agonist bromocriptine, which was a potent antimitogen of lactotrophs. The results suggest MAP kinase- and cyclic AMP/PKA-mediated signals converge at the level of p70S6k or its upstream.

本文研究了环磷酸腺苷/蛋白激酶A（cyclicAMP/protein kinase A，PKA）和MAP激酶级联两条信号转导途径在催乳素细胞增殖调控中的相互作用。(1)MAP激酶抑制剂PD 98059不仅能有效抑制胰岛素的促有丝分裂作用，还能有效抑制增加细胞内cAMP水平的毛喉素的促有丝分裂作用，这表明MAP激酶级联反应对cAMP/PKA的促有丝分裂作用是必需的。(2)PKA抑制剂H89和KT 5720不仅能有效抑制毛喉素的促有丝分裂作用，还能有效抑制胰岛素的促有丝分裂作用，这表明生长因子如胰岛素的促有丝分裂作用需要环AMP/PKA。(3)用选择性抗体对催乳素细胞中磷酸化MAP激酶进行免疫染色，以估计MAP激酶的活性。尽管磷酸化MAP激酶免疫反应性催乳细胞的数量被二丁酰环AMP或毛喉素改变，但磷酸化CREB免疫反应性催乳细胞的数量被毛喉素和胰岛素样生长因子-1增加。(4)p70 S6 k抑制剂雷帕霉素抑制胰岛素或毛喉素诱导的催乳细胞增殖以及生理上重要的有丝分裂原雌二醇诱导的增殖。雷帕霉素抑制胰岛素，但不毛喉素诱导的增殖的多巴胺激动剂溴隐亭，这是一种有效的抗有丝分裂的催乳细胞的存在下。结果表明MAP激酶和cAMP/PKA介导的信号在p70 S6 k或其上游水平会聚。