Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Mol Cell Biol. 2014 Jan;34(2):180-95. doi: 10.1128/MCB.01020-13. Epub 2013 Nov 4.
Transforming growth factor β (TGF-β) is a potent growth regulator and tumor suppressor in normal intestinal epithelium. Likewise, epithelial cell growth is controlled by rapid decay of growth-related mRNAs mediated through 3' untranslated region (UTR) AU-rich element (ARE) motifs. We demonstrate that treatment of nontransformed intestinal epithelial cells with TGF-β inhibited ARE-mRNA expression. This effect of TGF-β was promoted through increased assembly of cytoplasmic RNA processing (P) bodies where ARE-mRNA localization was observed. P-body formation was dependent on TGF-β/Smad signaling, as Smad3 deletion abrogated P-body formation. In concert with increased P-body formation, TGF-β induced expression of the ARE-binding protein tristetraprolin (TTP), which colocalized to P bodies. TTP expression was necessary for TGF-β-dependent P-body formation and promoted growth inhibition by TGF-β. The significance of this was observed in vivo, where colonic epithelium deficient in TGF-β/Smad signaling or TTP expression showed attenuated P-body levels. These results provide new insight into TGF-β's antiproliferative properties and identify TGF-β as a novel mRNA stability regulator in intestinal epithelium through its ability to promote TTP expression and subsequent P-body formation.
转化生长因子 β（TGF-β）是正常肠道上皮中的一种有效的生长调节剂和肿瘤抑制剂。同样，上皮细胞的生长受到通过 3'非翻译区（UTR）AU 丰富元件（ARE）基序介导的快速衰减的与生长相关的 mRNA 的控制。我们证明，用 TGF-β 处理非转化的肠道上皮细胞会抑制 ARE-mRNA 的表达。TGF-β 的这种作用是通过增加细胞质 RNA 处理（P）体的组装来促进的，在那里观察到 ARE-mRNA 的定位。P 体的形成依赖于 TGF-β/Smad 信号，因为 Smad3 的缺失消除了 P 体的形成。与 P 体形成增加一致，TGF-β 诱导 ARE 结合蛋白 tristetraprolin（TTP）的表达，TTP 与 P 体共定位。TTP 的表达是 TGF-β 依赖性 P 体形成所必需的，并促进 TGF-β 的生长抑制。在体内观察到了这一点，其中缺乏 TGF-β/Smad 信号或 TTP 表达的结肠上皮显示 P 体水平减弱。这些结果为 TGF-β 的抗增殖特性提供了新的见解，并通过其促进 TTP 表达和随后的 P 体形成的能力，将 TGF-β 鉴定为肠道上皮中的新型 mRNA 稳定性调节剂。
