Intracellular signal transduction pathways regulating proliferation of anterior pituitary cells

点击翻译按钮获取中文摘要

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.