Miskimins W K, King F, Miskimins R
University of South Dakota School of Medicine, Department of Biochemistry and Molecular Biology, Vermillion 57069, USA.
Cell Growth Differ. 1997 May;8(5):565-70.
Expression of the transferrin receptor is necessary for cells to progress through S-phase. The transferrin receptor gene promoter is activated as a delayed event following growth factor stimulation of quiescent fibroblasts. Serum stimulation in the presence of vanadate leads to superactivation of the transferrin receptor promoter, suggesting a role for tyrosine phosphorylation. Wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, a tyrosine kinase-regulated enzyme, blocks mitogen-dependent activation of the transferrin receptor promoter. Furthermore, wortmannin was able to block activation of this promoter when added several hours after serum stimulation of quiescent cells. This suggests that phosphatidylinositol 3-kinase may be required in mid to late G1 and that it is directly involved in a pathway leading to activation of the transferrin receptor promoter. This is further supported by the finding that the transferrin receptor promoter is much less responsive to mitogenic stimulation in cells that have been stably transfected with a dominant negative form of the phosphatidylinositol 3-kinase regulatory subunit. Activation of S6 kinase, an event known to be downstream of phosphatidylinositol 3-kinase activation, appears not to be involved in activation of the transferrin receptor promoter since no effect was observed by treatment of cells with rapamycin.
转铁蛋白受体的表达对于细胞进入S期是必需的。在静止的成纤维细胞受到生长因子刺激后，转铁蛋白受体基因启动子作为一个延迟事件被激活。在钒酸盐存在的情况下进行血清刺激会导致转铁蛋白受体启动子的超激活，提示酪氨酸磷酸化发挥了作用。渥曼青霉素是磷脂酰肌醇3激酶（一种酪氨酸激酶调节的酶）的强效抑制剂，它能阻断有丝分裂原依赖的转铁蛋白受体启动子的激活。此外，在静止细胞受到血清刺激数小时后添加渥曼青霉素，它仍能阻断该启动子的激活。这表明磷脂酰肌醇3激酶可能在G1期中期到后期是必需的，并且它直接参与了导致转铁蛋白受体启动子激活的一条信号通路。用磷脂酰肌醇3激酶调节亚基的显性负性形式稳定转染的细胞中，转铁蛋白受体启动子对有丝分裂原刺激的反应明显减弱，这一发现进一步支持了上述观点。由于用雷帕霉素处理细胞未观察到任何影响，所以已知在磷脂酰肌醇3激酶激活下游的S6激酶的激活似乎不参与转铁蛋白受体启动子的激活。
