Slingerland J M, Hengst L, Pan C H, Alexander D, Stampfer M R, Reed S I
Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037.
Mol Cell Biol. 1994 Jun;14(6):3683-94. doi: 10.1128/mcb.14.6.3683-3694.1994.
Transforming growth factor beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Cyclins E and A in association with Cdk2 have been shown to play a role in the G1-to-S phase transition in mammalian cells. We have studied the effects of TGF-beta-mediated growth arrest on G1/S cyclins E and A. Inhibition of cyclin A-associated kinase by TGF-beta is primarily due to a decrease in cyclin A mRNA and protein. By contrast, while TGF-beta inhibits accumulation of cyclin E mRNA, the reduction in cyclin E protein is minimal. Instead, we find that the activation of cyclin E-associated kinase that normally accompanies the G1-to-S phase transition is inhibited. A novel inhibitor of cyclin-Cdk complexes was detected in TGF-beta-treated cell lysates. Inhibition is mediated by a heat-stable protein that targets both Cdk2 and Cdc2 kinases. In G0-arrested cells, a similar inhibitor of Cdk2 kinase was detected. These data suggest the existence of an inhibitor of cyclin-dependent kinases induced under different conditions to mediate antiproliferative responses.
转化生长因子β（TGF-β）是上皮细胞生长的强效抑制剂。细胞周期蛋白E和A与Cdk2相关联，已被证明在哺乳动物细胞的G1期到S期转变中发挥作用。我们研究了TGF-β介导的生长停滞对G1/S细胞周期蛋白E和A的影响。TGF-β对细胞周期蛋白A相关激酶的抑制主要是由于细胞周期蛋白A mRNA和蛋白质的减少。相比之下，虽然TGF-β抑制细胞周期蛋白E mRNA的积累，但细胞周期蛋白E蛋白的减少却微乎其微。相反，我们发现通常伴随G1期到S期转变的细胞周期蛋白E相关激酶的激活受到抑制。在TGF-β处理的细胞裂解物中检测到一种新型的细胞周期蛋白-Cdk复合物抑制剂。抑制作用由一种靶向Cdk2和Cdc2激酶的热稳定蛋白介导。在G0期停滞的细胞中，检测到一种类似的Cdk2激酶抑制剂。这些数据表明存在一种在不同条件下诱导产生的细胞周期蛋白依赖性激酶抑制剂，以介导抗增殖反应。
