Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Mol Cell. 2014 Jul 3;55(1):59-72. doi: 10.1016/j.molcel.2014.05.007. Epub 2014 Jun 5.
DNA damage can result in a transient cell-cycle arrest or lead to permanent cell-cycle withdrawal. Here we show that the decision to irreversibly withdraw from the cell cycle is made within a few hours following damage in G2 cells. This permanent arrest is dependent on induction of p53 and p21, resulting in the nuclear retention of Cyclin B1. This rapid response is followed by the activation of the APC/C(Cdh1) (the anaphase-promoting complex/cyclosome and its coactivator Cdh1) several hours later. Inhibition of APC/C(Cdh1) activity fails to prevent cell-cycle withdrawal, whereas preventing nuclear retention of Cyclin B1 does allow cells to remain in cycle. Importantly, transient induction of p53 in G2 cells is sufficient to induce senescence. Taken together, these results indicate that a rapid and transient pulse of p53 in G2 can drive nuclear retention of Cyclin B1 as the first irreversible step in the onset of senescence.
DNA 损伤可导致细胞周期短暂停滞或导致细胞周期永久性退出。在这里，我们发现细胞在 G2 期受到损伤后数小时内做出不可逆地退出细胞周期的决定。这种永久性阻滞依赖于 p53 和 p21 的诱导，导致细胞周期蛋白 B1 的核内滞留。数小时后，快速反应后 APC/C(Cdh1)（有丝分裂促进复合物/细胞周期蛋白和其共激活因子 Cdh1）被激活。随后，抑制 APC/C(Cdh1) 的活性并不能阻止细胞周期的退出，而阻止细胞周期蛋白 B1 的核内滞留则允许细胞继续留在细胞周期中。重要的是，G2 期 p53 的短暂诱导足以诱导衰老。总之，这些结果表明，G2 期中 p53 的快速短暂脉冲可驱动细胞周期蛋白 B1 的核内滞留，作为衰老起始的第一个不可逆步骤。
