Ludwig Institute for Cancer Research, Uppsala University, Box 595 Biomedical Center, SE-751 24 Uppsala, Sweden.
Mol Cell. 2010 Nov 24;40(4):521-32. doi: 10.1016/j.molcel.2010.10.029.
The versatile cytokine transforming growth factor β (TGF-β) regulates cellular growth, differentiation, and migration during embryonic development and adult tissue homeostasis. Activation of TGF-β receptors leads to phosphorylation of Smad2 and Smad3, which oligomerize with Smad4 and accumulate in the nucleus where they recognize gene regulatory regions and orchestrate transcription. Termination of Smad-activated transcription involves Smad dephosphorylation, nuclear export, or ubiquitin-mediated degradation. In an unbiased proteomic screen, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a Smad-interacting partner. PARP-1 dissociates Smad complexes from DNA by ADP-ribosylating Smad3 and Smad4, which attenuates Smad-specific gene responses and TGF-β-induced epithelial-mesenchymal transition. Thus, our results identify ADP-ribosylation of Smad proteins by PARP-1 as a key step in controlling the strength and duration of Smad-mediated transcription.
多功能细胞因子转化生长因子 β（TGF-β）在胚胎发育和成人组织稳态过程中调节细胞生长、分化和迁移。TGF-β 受体的激活导致 Smad2 和 Smad3 的磷酸化，它们与 Smad4 形成寡聚体并在核内积累，在核内识别基因调控区域并协调转录。Smad 激活转录的终止涉及 Smad 去磷酸化、核输出或泛素介导的降解。在一项无偏的蛋白质组学筛选中，我们鉴定出聚（ADP-核糖）聚合酶 1（PARP-1）是 Smad 的相互作用伙伴。PARP-1 通过 ADP-核糖基化 Smad3 和 Smad4 从 DNA 上解离 Smad 复合物，从而减弱 Smad 特异性基因反应和 TGF-β 诱导的上皮-间充质转化。因此，我们的结果表明，PARP-1 对 Smad 蛋白的 ADP-核糖基化是控制 Smad 介导的转录强度和持续时间的关键步骤。
