SMAD2/SMAD3:SMAD4 异二聚体调节转录
中文名称
通路描述
磷酸化的 SMAD2 和/或 SMAD3 与 SMAD4 形成异二聚体，该复合物转位至细胞核（Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003）。在细胞核内，SMAD2 和 SMAD3 的 linker 区域可被 CDK8（与 cyclin C 结合）或 CDK9（与 cyclin T 结合）磷酸化。CDK8/CDK9 介导的 SMAD2/3 磷酸化增强了 SMAD2/3:SMAD4 复合物的转录活性，但也使其易被泛素化并导致降解（Alarcon et al. 2009）。SMAD2/3:SMAD4 复合物的转位可被其他蛋白质如 WWTR1 辅助；在人类胚胎细胞中，WWTR1（TAZ）结合 SMAD2/3:SMAD4 异二聚体，介导 TGF-β依赖性 SMAD2/3:SMAD4 的核积累。WWTR1 与 SMAD2/3:SMAD4 复合物的结合可结合 SMAD7 和 SERPINE1（PAI-1）基因的启动子，刺激其转录（Varelas et al. 2008）。SMAD7 的转录激活代表 TGF-β受体信号通路中的负反馈机制。SMAD7 可被 RNF111 泛素化酶（Arkadia）下调，该酶结合并泛素化 SMAD7，将其靶向降解（Koinuma et al. 2003）。SMAD2/3:SMAD4 异二聚体还结合 RBL1（p107）、E2F4/5 和 TFDP1/2（DP1/2）的复合物，该复合物结合 MYC 启动子并抑制 MYC 转录。MYC 转录的抑制有助于 TGF-β的抗增殖效应（Chen et al. 2002）。SMAD2/3:SMAD4 异二聚体还与转录因子 SP1 结合。SMAD2/3:SMAD4:SP1 复合物刺激 CDK 抑制剂 CDKN2B（p15-INK4B）的转录，这也有助于 TGF-β的抗增殖效应（Feng et al. 2000）。MEN1（menin），一种在 MEN1 综合征中突变的转录因子肿瘤抑制基因，与 SMAD2/3:SMAD4 异二聚体形成复合物，但 SMAD2/3:SMAD4:MEN1 的转录靶标尚未阐明（Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012）。JUNB 也是 SMAD2/3:SMAD4 复合物的已知转录靶标（Wong et al. 1999）。
英文描述
CDC6 association with the ORC:origin complex Cdc6 is a regulator of DNA replication initiation in both yeasts and human cells (Mendez and Stillman 2000), but its mechanism of action differs between the two systems. Genetic studies in budding yeast (S. cerevisiae) and fission yeast (S. pombe) indicate that the normal function of Cdc6 protein is required to restrict DNA replication to once per cell cycle. Specifically, Cdc6 may function as an ATPase switch linked to Mcm2-7:Cdt1 association with the Cdc6:ORC:origin complex (Lee and Bell 2000). In S. cerevisiae, Cdc6 protein is expressed late in the M phase of the cell cycle and, in cells with a prolonged G1 phase, late in G1. This protein has a short half-life, and is destroyed by ubiquitin-mediated proteolysis, mediated by the SCF complex (Piatti et al. 1995, Drury et al. 1997, Drury et al. 2000, Perkins et al. 2001). Human Cdc6 protein levels are reduced early in G1 but otherwise are constant throughout the cell cycle (Petersen et al. 2000). Some reports have suggested that after cells enter S phase, Cdc6 is phosphorylated, excluded from the nucleus and subject to ubiquitination and degradation (Saha et al. 1998, Jiang et al. 1999, Petersen et al. 1999). Replenishing Cdc6 protein levels during G1 appears to be regulated by E2F transcription factors (Yan et al. 1998).
所含基因
8 个基因