Krakowski Ariel R, Laboureau Julien, Mauviel Alain, Bissell Mina J, Luo Kunxin
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12437-42. doi: 10.1073/pnas.0504107102. Epub 2005 Aug 18.
TGF-beta is a ubiquitously expressed cytokine that signals through the Smad proteins to regulate many diverse cellular processes. SnoN is an important negative regulator of Smad signaling. It has been described as a nuclear protein, based on studies of ectopically expressed SnoN and endogenous SnoN in cancer cell lines. In the nucleus, SnoN binds to Smad2, Smad3, and Smad4 and represses their ability to activate transcription of TGF-beta target genes through multiple mechanisms. Here, we show that, whereas SnoN is localized exclusively in the nucleus in cancer tissues or cells, in normal tissues and nontumorigenic or primary epithelial cells, SnoN is predominantly cytoplasmic. Upon morphological differentiation or cell-cycle arrest, SnoN translocates into the nucleus. In contrast to nuclear SnoN that represses the transcriptional activity of the Smad complexes, cytoplasmic SnoN antagonizes TGF-beta signaling by sequestering the Smad proteins in the cytoplasm. Interestingly, cytoplasmic SnoN is resistant to TGF-beta-induced degradation and therefore is more potent than nuclear SnoN in repressing TGF-beta signaling. Thus, we have identified a mechanism of regulation of TGF-beta signaling via differential subcellular localization of SnoN that is likely to produce different patterns of downstream TGF-beta responses and may influence the proliferation or differentiation states of epithelial cells.
转化生长因子-β（TGF-β）是一种广泛表达的细胞因子，它通过Smad蛋白发出信号，调节许多不同的细胞过程。SnoN是Smad信号的重要负调节因子。基于对癌细胞系中异位表达的SnoN和内源性SnoN的研究，它被描述为一种核蛋白。在细胞核中，SnoN与Smad2、Smad3和Smad4结合，并通过多种机制抑制它们激活TGF-β靶基因转录的能力。在这里，我们表明，虽然SnoN仅定位于癌组织或细胞的细胞核中，但在正常组织以及非致瘤性或原代表皮细胞中，SnoN主要位于细胞质中。在形态分化或细胞周期停滞时，SnoN会转运到细胞核中。与抑制Smad复合物转录活性的核SnoN不同，细胞质中的SnoN通过将Smad蛋白隔离在细胞质中来拮抗TGF-β信号。有趣的是，细胞质中的SnoN对TGF-β诱导的降解具有抗性，因此在抑制TGF-β信号方面比核SnoN更有效。因此，我们确定了一种通过SnoN的亚细胞定位差异来调节TGF-β信号的机制，这种机制可能会产生不同的下游TGF-β反应模式，并可能影响上皮细胞的增殖或分化状态。
