Takahashi-Yanaga Fumi, Sasaguri Toshiyuki
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Cell Signal. 2008 Apr;20(4):581-9. doi: 10.1016/j.cellsig.2007.10.018. Epub 2007 Oct 23.
Cyclin D1 is known as a proto-oncogene whose gene amplification and protein overexpression are frequently observed in tumor cells. It acts as a mitogenic signal sensor and is expressed as a delayed-early response to many mitogenic signals. Cyclin-dependent kinases (CDKs) 4 and 6 are cyclin D1 binding partners, and activated cyclin D1/CDK4 and cyclin D1/CDK6 complex phosphorylate the retinoblastoma protein to induce the expression of target genes essential for S phase entry, resulting in facilitation of the progression from G1 to S phase. As well as acting as a positive regulator of the cell cycle, cyclin D1 is known to bind and modulate the actions of several transcription factors. Since the protein level of cyclin D1 reflects cell cycle progression, the rates of protein production and degradation are strictly regulated. Glycogen synthase kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been shown to play an important role in the determination of cyclin D1 expression level by regulating mRNA transcription and protein degradation. This review highlights the regulatory mechanisms of cyclin D1 expression level, with special attention to the involvement of GSK-3beta.
细胞周期蛋白D1被认为是一种原癌基因，其基因扩增和蛋白过表达在肿瘤细胞中经常被观察到。它作为一种促有丝分裂信号传感器，对许多促有丝分裂信号作出延迟早期反应而表达。细胞周期蛋白依赖性激酶（CDK）4和6是细胞周期蛋白D1的结合伙伴，活化的细胞周期蛋白D1/CDK4和细胞周期蛋白D1/CDK6复合物使视网膜母细胞瘤蛋白磷酸化，以诱导进入S期所必需的靶基因的表达，从而促进从G1期到S期的进程。除了作为细胞周期的正调控因子外，细胞周期蛋白D1还已知可结合并调节几种转录因子的作用。由于细胞周期蛋白D1的蛋白水平反映细胞周期进程，其蛋白产生和降解速率受到严格调控。糖原合酶激酶-3β（GSK-3β），一种丝氨酸/苏氨酸蛋白激酶，已被证明通过调节mRNA转录和蛋白降解在决定细胞周期蛋白D1表达水平方面发挥重要作用。本综述重点介绍细胞周期蛋白D1表达水平的调控机制，特别关注GSK-3β的参与情况。
