Persengiev S P, Li J, Poulin M L, Kilpatrick D L
Department of Cellular and Molecular Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Oncogene. 2001 Aug 23;20(37):5124-31. doi: 10.1038/sj.onc.1204663.
E2Fs play a central role in cell proliferation and growth arrest through their ability to regulate genes involved in cell cycle progression, arrest and apoptosis. Recent studies further indicate that this family of transcriptional regulators participate in cell fate/differentiation events. They are thus likely to have a prominent role in controlling the terminal differentiation process and its irreversibility. Here we have specifically examined the role of E2F2 in neuronal differentiation using a gain-of-function approach. Endogenous E2F2 increased in PC12 cells in response to nerve growth factor (NGF) and was also expressed in cerebellar granule neurons undergoing terminal differentiation. While PC12 cells normally undergo reversible dedifferentiation and cell cycle re-entry upon NGF removal, forced expression of E2F2 inhibited these events and induced apoptosis. Thus, E2F2 converted PC12-derived neurons from a reversible to a 'terminally' differentiated, NGF-dependent state, analogous to postmitotic sympathetic neurons. This contrasts with the effects of E2F4, which enhances the differentiation state of PC12 cells without affecting cell cycle parameters or survival. These results indicate that E2F2 may have a unique role in maintaining the postmitotic state of terminally differentiated neurons, and may participate in apoptosis in neurons attempting to re-enter the cell cycle. It may also be potentially useful in promoting the terminally arrested/differentiated state of tumor cells.
E2F转录因子通过调节参与细胞周期进程、停滞及凋亡的基因，在细胞增殖和生长停滞中发挥核心作用。近期研究进一步表明，这一家族的转录调节因子参与细胞命运/分化事件。因此，它们可能在控制终末分化过程及其不可逆性方面发挥重要作用。在此，我们使用功能获得法特异性研究了E2F2在神经元分化中的作用。在神经生长因子（NGF）作用下，PC12细胞内源性E2F2增加，并且其在经历终末分化的小脑颗粒神经元中也有表达。虽然正常情况下，去除NGF后PC12细胞会发生可逆的去分化并重新进入细胞周期，但强制表达E2F2会抑制这些事件并诱导凋亡。因此，E2F2将源自PC12的神经元从可逆状态转变为“终末”分化的、依赖NGF的状态，类似于有丝分裂后的交感神经元。这与E2F4的作用形成对比，E2F4可增强PC12细胞的分化状态，但不影响细胞周期参数或细胞存活。这些结果表明，E2F2可能在维持终末分化神经元的有丝分裂后状态中具有独特作用，并可能参与试图重新进入细胞周期的神经元的凋亡过程。它在促进肿瘤细胞的终末停滞/分化状态方面也可能具有潜在用途。
