Shibutani Shusaku T, de la Cruz Aida Flor A, Tran Vuong, Turbyfill William J, Reis Tânia, Edgar Bruce A, Duronio Robert J
Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
Dev Cell. 2008 Dec;15(6):890-900. doi: 10.1016/j.devcel.2008.10.003.
E2F transcription factors are key regulators of cell proliferation that are inhibited by pRb family tumor suppressors. pRb-independent modes of E2F inhibition have also been described, but their contribution to animal development and tumor suppression is unclear. Here, we show that S phase-specific destruction of Drosophila E2f1 provides a novel mechanism for cell cycle regulation. E2f1 destruction is mediated by a PCNA-interacting-protein (PIP) motif in E2f1 and the Cul4(Cdt2) E3 ubiquitin ligase and requires the Dp dimerization partner but not direct Cdk phosphorylation or Rbf1 binding. E2f1 lacking a functional PIP motif accumulates inappropriately during S phase and is more potent than wild-type E2f1 at accelerating cell cycle progression and inducing apoptosis. Thus, S phase-coupled destruction is a key negative regulator of E2f1 activity. We propose that pRb-independent inhibition of E2F during S phase is an evolutionarily conserved feature of the metazoan cell cycle that is necessary for development.
E2F转录因子是细胞增殖的关键调节因子，受pRb家族肿瘤抑制因子的抑制。也有报道称存在不依赖pRb的E2F抑制模式，但其对动物发育和肿瘤抑制的作用尚不清楚。在这里，我们表明果蝇E2f1在S期的特异性破坏为细胞周期调控提供了一种新机制。E2f1的破坏由E2f1中的PCNA相互作用蛋白（PIP）基序和Cul4（Cdt2）E3泛素连接酶介导，需要Dp二聚体伙伴，但不需要直接的Cdk磷酸化或Rbf1结合。缺乏功能性PIP基序的E2f1在S期不适当积累，在加速细胞周期进程和诱导凋亡方面比野生型E2f1更有效。因此，S期偶联破坏是E2f1活性的关键负调节因子。我们提出，在S期不依赖pRb对E2F的抑制是后生动物细胞周期中进化保守的特征，对发育是必需的。
