Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, Hubei 430022, People's Republic of China; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Biochem Biophys Res Commun. 2014 Jul 18;450(1):409-15. doi: 10.1016/j.bbrc.2014.05.125. Epub 2014 Jun 2.
We previously reported that a novel WD-40 domain-containing protein, p44/WDR77, drives quiescent epithelial cells to re-enter the cell cycle and plays an essential role for growth of lung and prostate cancer cells. Transforming growth factor beta (TGFβ) signaling is important in the maintenance of non-transformed cells in the quiescent or slowly cycling stage. However, both non-transformed proliferating cells and human cancer cells are non-responsive to endogenous TGFβ signaling. The mechanism by which proliferating cells become refractory to TGFβ inhibition is not well established. Here, we found that silencing p44/WDR77 increased cellular sensitivity to TGFβ signaling and that this was inversely correlated with decreased cell proliferation. Smad2 or 3 phosphorylation, TGFβ-mediated transcription, and TGFβ2 and TGFβ receptor type II (TβRII) expression were dramatically induced by silencing of p44/WDR77. These data support the hypothesis that p44/WDR77 down-regulates the expression of the TGFβ ligand and its receptor, thereby leading to a cellular non-response to TGFβ signaling. Finally, we found that p44/WDR77 expression was correlated with cell proliferation and decreased TGFβ signaling during lung tumorigenesis. Together, these results suggest that p44/WDR77 expression causes the non-sensitivity of proliferating cells to TGFβ signaling, thereby contributing to cellular proliferation during lung tumorigenesis.
我们之前报道过一种新型 WD-40 结构域蛋白 p44/WDR77，它能驱使静止的上皮细胞重新进入细胞周期，并对肺和前列腺癌细胞的生长起关键作用。转化生长因子 β（TGFβ）信号在维持静止或缓慢循环阶段的未转化细胞中非常重要。然而，未转化的增殖细胞和人类癌细胞都对内源性 TGFβ 信号无反应。增殖细胞对 TGFβ 抑制作用产生抗性的机制尚未完全确定。在这里，我们发现沉默 p44/WDR77 增加了细胞对 TGFβ 信号的敏感性，而这与细胞增殖的降低呈负相关。p44/WDR77 沉默后，Smad2 或 3 磷酸化、TGFβ 介导的转录以及 TGFβ2 和 TGFβ 受体 II（TβRII）的表达均显著增加。这些数据支持以下假设：p44/WDR77 下调 TGFβ 配体及其受体的表达，从而导致细胞对 TGFβ 信号无反应。最后，我们发现 p44/WDR77 表达与肺肿瘤发生过程中的细胞增殖和 TGFβ 信号降低相关。总之，这些结果表明 p44/WDR77 的表达导致增殖细胞对 TGFβ 信号不敏感，从而促进了肺肿瘤发生过程中的细胞增殖。
