Zhang Fan, Mönkkönen Mia, Roth Stina, Laiho Marikki
Haartman Institute, Department of Virology and Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Central Hospital Laboratory Diagnostics, Finland.
Exp Cell Res. 2002 Dec 10;281(2):190-6. doi: 10.1006/excr.2002.5670.
Transforming growth factor-beta (TGF-beta) induces a potent G(1)/S-phase cell cycle arrest of epithelial cells by inhibiting the activities of cyclin D- and cyclin E-associated kinase complexes. Downregulation of the kinase activities is mediated by induction of cyclin dependent kinase (CDK) inhibitor p15(Ink4b) which blocks CDK4 and CDK6 kinases and leads to binding of p27(Kip1) to CDK2-cyclin E complex. Levels of several of these factors are controlled by the ubiquitin-proteasome pathway. We demonstrate here that proteasomal inhibitors release the cells from TGF-beta imposed G(1)-phase arrest and instigate the entry of the cells into S-phase. Proteasomal inhibitors are shown to specifically increase the activity of the cyclin D-kinase complex by increasing the levels of p27(Kip1) and cyclin D and by maintaining CDK4/6 protein levels leading to phosphorylation of the retinoblastoma protein without increasing cyclin E-associated kinase activity. The results indicate caution in the potential therapeutic use of the proteasome inhibitors due to unscheduled initiation of DNA replication in the presence of a physiological growth inhibitor.
转化生长因子-β（TGF-β）通过抑制细胞周期蛋白D和细胞周期蛋白E相关激酶复合物的活性，诱导上皮细胞发生有效的G1/S期细胞周期阻滞。激酶活性的下调是由细胞周期蛋白依赖性激酶（CDK）抑制剂p15（Ink4b）的诱导介导的，p15（Ink4b）可阻断CDK4和CDK6激酶，并导致p27（Kip1）与CDK2-细胞周期蛋白E复合物结合。这些因子中的几种水平受泛素-蛋白酶体途径控制。我们在此证明，蛋白酶体抑制剂可使细胞从TGF-β诱导的G1期阻滞中释放出来，并促使细胞进入S期。蛋白酶体抑制剂通过增加p27（Kip1）和细胞周期蛋白D的水平，并维持CDK4/6蛋白水平，从而导致视网膜母细胞瘤蛋白磷酸化，而不增加细胞周期蛋白E相关激酶活性，来特异性增加细胞周期蛋白D激酶复合物的活性。结果表明，由于在存在生理性生长抑制剂的情况下意外启动DNA复制，蛋白酶体抑制剂在潜在治疗应用中需谨慎使用。
