School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
Oncogene. 2010 Sep 23;29(38):5322-8. doi: 10.1038/onc.2010.278. Epub 2010 Jul 12.
Transforming growth factor-β (TGFβ) signaling regulates multiple cellular processes, including extracellular matrix production, cell growth, apoptosis and differentiation. Dysfunction of TGFβ signaling has been implicated in various human disorders ranging from vascular diseases to cancer. TGFβ signaling is negatively regulated by the transcriptional repressor TGFβ-induced factor 1 (TGIF1). The tumor suppressor Fbxw7 is the substrate-recognition factor of a ubiquitin ligase that targets multiple proteins for degradation, including c-Myc, cyclin E, c-Jun and Notch. Here, we describe that TGIF1 is targeted for degradation by Fbxw7 in a phosphorylation-dependent manner. Inactivation of Fbxw7 results in the accumulation of phosphorylated TGIF1 molecules and repression of TGFβ-dependent transcription. Cancer cell lines with inactivating mutations in Fbxw7 show enhanced levels of TGIF1 and attenuated TGFβ-dependent signaling. Importantly, inactivation of Fbxw7 attenuates TGFβ-dependent regulation of cell growth and migration. Taken together, our results suggest that Fbxw7 is a novel regulator of TGFβ signaling.
转化生长因子-β（TGFβ）信号通路调节多种细胞过程，包括细胞外基质的产生、细胞生长、凋亡和分化。TGFβ信号通路的功能障碍与多种人类疾病有关，从血管疾病到癌症。TGFβ信号通路受到转录抑制因子 TGFβ诱导因子 1（TGIF1）的负调控。肿瘤抑制因子 Fbxw7 是一种泛素连接酶的底物识别因子，该酶可以靶向多种蛋白质进行降解，包括 c-Myc、细胞周期蛋白 E、c-Jun 和 Notch。在这里，我们描述了 TGIF1 可以通过磷酸化依赖性方式被 Fbxw7 靶向降解。Fbxw7 的失活会导致磷酸化 TGIF1 分子的积累和 TGFβ 依赖性转录的抑制。在 Fbxw7 中具有失活突变的癌细胞系显示出 TGIF1 水平升高和 TGFβ 依赖性信号转导减弱。重要的是，Fbxw7 的失活会减弱 TGFβ 依赖性对细胞生长和迁移的调节。总之，我们的研究结果表明，Fbxw7 是 TGFβ 信号通路的一种新型调节因子。
