Hansen Ulla, Owens Laura, Saxena Utsav H
Department of Biology and Program in Molecular Biology, Cell Biology and Biochemistry, Boston University, Boston, MA 02215, USA.
Cell Cycle. 2009 Jul 15;8(14):2146-51. doi: 10.4161/cc.8.14.9089. Epub 2009 Jul 21.
Cell cycle progression in mammalian cells from G(1) into S phase requires sensing and integration of multiple inputs, in order to determine whether to continue to cellular DNA replication and subsequently, to cell division. Passage to S requires transition through the restriction point, which at a molecular level consists of a bistable switch involving E2Fs and pRb family members. At the G(1)/S boundary, a number of genes essential for DNA replication and cell cycle progression are upregulated, promoting entry into S phase. Although the activating E2Fs are the most extensively characterized transcription factors driving G(1)/S expression, LSF is also a transcription factor essential for stimulating G(1)/S gene expression. A critical LSF target gene at this stage, Tyms, encodes thymidylate synthetase. In investigating how LSF is activated in a cell cycle-dependent manner, we recently identified a novel time delay mechanism for regulating its activity during G(1) progression, which is apparently independent of the E2F/pRb axis. This involves inhibition of LSF in early G(1) by two major proliferative signaling pathways: ERK and cyclin C/CDK, followed by gradual dephosphorylation during mid- to late-G(1). Whether LSF and E2F act independently or in concert to promote G(1)/S progression remains to be determined.
哺乳动物细胞从G(1)期进入S期的细胞周期进程需要感知和整合多种输入信号，以便确定是否继续进行细胞DNA复制以及随后的细胞分裂。进入S期需要通过限制点，在分子水平上，限制点由一个双稳态开关组成，涉及E2F和pRb家族成员。在G(1)/S边界，一些对DNA复制和细胞周期进程至关重要的基因被上调，促进细胞进入S期。尽管激活型E2F是驱动G(1)/S期基因表达的最具特征的转录因子，但LSF也是刺激G(1)/S期基因表达所必需的转录因子。在此阶段，一个关键的LSF靶基因Tyms编码胸苷酸合成酶。在研究LSF如何以细胞周期依赖性方式被激活时，我们最近发现了一种在G(1)期进程中调节其活性的新型时间延迟机制，该机制显然独立于E2F/pRb轴。这涉及在G(1)早期通过两种主要的增殖信号通路ERK和细胞周期蛋白C/CDK对LSF的抑制，随后在G(1)中期到后期逐渐去磷酸化。LSF和E2F是独立还是协同作用来促进G(1)/S期进程仍有待确定。
