Leicht M, Simm A, Bertsch G, Hoppe J
Theodor-Boveri-Institut für Biowissenschaften (Biozentrum), Universität, Würzburg, Germany.
Cell Growth Differ. 1996 Sep;7(9):1199-209.
At low concentrations (50 nM), okadaic acid (OA), an inhibitor of phosphatases 1 and 2A, inhibits platelet-derived growth factor-induced cell proliferation in late G1 (A. Simm et al., Exp. Cell Res., 210: 160-165, 1994). This inhibition is caused by the interference of OA in the induction and activation of the cell division protein kinases cdk1 and cdk2. OA alone has no effect on cell number, but induces a pronounced increase in cell size. The OA-induced hypertrophy can be divided into two phases. The first phase is characterized by a swelling of the cells. This increase in cellular volume is not accompanied by a change in the level of cellular macromolecules, i.e., protein and RNA. Inhibitor studies indicated a possible role of the Na+/H+ antiporter and Cl- channels in this process. In the second phase, an increase in the cellular protein and RNA content was observed along with a minor change in cell volume. To delineate a possible signaling pathway, the involvement of numerous protein kinases was analyzed. Low concentrations of OA lead to pronounced and sustained activation of the p70S6 kinase. There was little or no effect on various other kinases that can be activated by extracellular signals, e.g., mitogen-activated kinase, ribosomal S6 kinase, or other S6 peptide kinases. Likewise, at these concentrations, OA did not activate the genes for fos, myc, or ornithine decarboxylase. At very low concentrations (ED50, 0.5 nM), rapamycin, a specific inhibitor of the activation of p70S6 kinase, reversed the activation of the p70S6 kinase and the enhancement of RNA synthesis and partially the increase in cell volume and protein synthesis. The OA-induced hypertrophy of AKR-2B fibroblasts may serve as a model system for investigations aimed at the identification of signaling pathways leading to hypertrophy of differentiated nonproliferating cells.
在低浓度（50纳摩尔）时，冈田酸（OA），一种磷酸酶1和2A的抑制剂，抑制血小板衍生生长因子诱导的G1晚期细胞增殖（A. 西姆等人，《实验细胞研究》，210: 160 - 165，1994）。这种抑制是由OA干扰细胞分裂蛋白激酶cdk1和cdk2的诱导和激活引起的。单独的OA对细胞数量没有影响，但会导致细胞大小显著增加。OA诱导的肥大可分为两个阶段。第一阶段的特征是细胞肿胀。细胞体积的这种增加并不伴随着细胞大分子（即蛋白质和RNA）水平的变化。抑制剂研究表明Na+/H+反向转运体和Cl-通道在这个过程中可能发挥作用。在第二阶段，观察到细胞蛋白质和RNA含量增加，同时细胞体积有轻微变化。为了确定可能的信号通路，分析了多种蛋白激酶的参与情况。低浓度的OA导致p70S6激酶显著且持续的激活。对其他各种可被细胞外信号激活的激酶，如丝裂原激活激酶、核糖体S6激酶或其他S6肽激酶，几乎没有影响。同样，在这些浓度下，OA也没有激活fos、myc或鸟氨酸脱羧酶的基因。在非常低的浓度（半数有效剂量，0.5纳摩尔）时，雷帕霉素，一种p70S6激酶激活的特异性抑制剂，逆转了p70S6激酶的激活以及RNA合成的增强，并部分逆转了细胞体积和蛋白质合成的增加。OA诱导的AKR - 2B成纤维细胞肥大可作为一个模型系统，用于旨在确定导致分化的非增殖细胞肥大的信号通路的研究。
