Cytoplasmic SnoN in normal tissues and nonmalignant cells antagonizes TGF-β signaling by sequestration of the Smad proteins
Cytoplasmic SnoN in normal tissues and nonmalignant cells antagonizes TGF-β signaling by sequestration of the Smad proteins
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DOI：
10.1073/pnas.0504107102
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发表时间：
2005-08-30
影响因子：
11.1
通讯作者：
Luo, KX
中科院分区：
文献类型：
--
作者：
Krakowski, AR;Laboureau, J;Luo, KX
TGF-β是一种广泛表达的细胞因子，其通过Smad蛋白发出信号以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和同源性SnoN的研究，其已被描述为核蛋白。在细胞核中，SnoN与Smad 2、Smad 3和Smad 4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，而SnoN是专门定位于细胞核中的癌组织或细胞，在正常组织和非致瘤性或原代上皮细胞，SnoN主要是细胞质。在形态分化或细胞周期停滞时，SnoN易位到细胞核中。与抑制Smad复合物的转录活性的核SnoN相反，细胞质SnoN通过在细胞质中隔离Smad蛋白来拮抗TGF-β信号传导。有趣的是，细胞质SnoN对TGF-β诱导的降解具有抗性，因此在抑制TGF-β信号传导方面比细胞核SnoN更有效。因此，我们已经确定了通过SnoN的差异亚细胞定位调节TGF-β信号传导的机制，其可能产生不同模式的下游TGF-β反应，并可能影响上皮细胞的增殖或分化状态。
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 enclogenous 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.