Toronto Western Research Institute, University Health Network, Department of Ophthalmology, and Laboratory Medicine and Pathobiology, University of Toronto, Ontario M5T 2S8, Canada.
Nature. 2009 Dec 17;462(7275):925-9. doi: 10.1038/nature08544.
The activating E2f transcription factors (E2f1, E2f2 and E2f3) induce transcription and are widely viewed as essential positive cell cycle regulators. Indeed, they drive cells out of quiescence, and the 'cancer cell cycle' in Rb1 null cells is E2f-dependent. Absence of activating E2fs in flies or mammalian fibroblasts causes cell cycle arrest, but this block is alleviated by removing repressive E2f or the tumour suppressor p53, respectively. Thus, whether activating E2fs are indispensable for normal division is an area of debate. Activating E2fs are also well known pro-apoptotic factors, providing a defence against oncogenesis, yet E2f1 can limit irradiation-induced apoptosis. In flies this occurs through repression of hid (also called Wrinkled; Smac/Diablo in mammals). However, in mammals the mechanism is unclear because Smac/Diablo is induced, not repressed, by E2f1, and in keratinocytes survival is promoted indirectly through induction of DNA repair targets. Thus, a direct pro-survival function for E2f1-3 and/or its relevance beyond irradiation has not been established. To address E2f1-3 function in normal cells in vivo we focused on the mouse retina, which is a relatively simple central nervous system component that can be manipulated genetically without compromising viability and has provided considerable insight into development and cancer. Here we show that unlike fibroblasts, E2f1-3 null retinal progenitor cells or activated Müller glia can divide. We attribute this effect to functional interchangeability with Mycn. However, loss of activating E2fs caused downregulation of the p53 deacetylase Sirt1, p53 hyperacetylation and elevated apoptosis, establishing a novel E2f-Sirt1-p53 survival axis in vivo. Thus, activating E2fs are not universally required for normal mammalian cell division, but have an unexpected pro-survival role in development.
激活的 E2f 转录因子（E2f1、E2f2 和 E2f3）诱导转录，被广泛认为是细胞周期的关键正向调控因子。事实上，它们促使细胞从静止期进入细胞周期，并且在 Rb1 缺失的细胞中，“癌细胞周期”依赖于 E2f。在果蝇或哺乳动物成纤维细胞中缺乏激活的 E2f 会导致细胞周期停滞，但通过分别去除抑制性 E2f 或肿瘤抑制因子 p53，可以缓解这种阻滞。因此，激活的 E2f 是否对正常分裂是不可或缺的，这是一个有争议的领域。激活的 E2f 也是众所周知的促凋亡因子，为防止癌变提供了防御机制，但 E2f1 可以限制辐射诱导的细胞凋亡。在果蝇中，这是通过抑制 hid（也称为 Wrinkled；在哺乳动物中称为 Smac/Diablo）来实现的。然而，在哺乳动物中，其机制尚不清楚，因为 Smac/Diablo 被 E2f1 诱导，而不是抑制，并且在角质形成细胞中，生存是通过间接诱导 DNA 修复靶标来促进的。因此，E2f1-3 的直接促生存功能及其在照射之外的相关性尚未得到证实。为了在体内研究正常细胞中 E2f1-3 的功能，我们将重点放在小鼠视网膜上，视网膜是一种相对简单的中枢神经系统成分，可以在不影响其活力的情况下进行遗传操作，并为发育和癌症提供了重要的见解。在这里，我们发现与成纤维细胞不同，E2f1-3 缺失的视网膜祖细胞或激活的 Müller 胶质细胞可以分裂。我们将这种效应归因于与 Mycn 的功能可互换性。然而，激活的 E2f 的缺失导致 p53 去乙酰化酶 Sirt1 的下调、p53 乙酰化增加和凋亡增加，在体内建立了一个新的 E2f-Sirt1-p53 生存轴。因此，激活的 E2f 并非普遍需要正常的哺乳动物细胞分裂，但在发育过程中具有意想不到的促生存作用。
