Ramel M-C, Emery C M, Foulger R, Goberdhan D C I, van den Heuvel M, Wilson C
Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford OX1 3QX, UK.
Mech Dev. 2007 Apr;124(4):304-17. doi: 10.1016/j.mod.2006.12.006. Epub 2006 Dec 29.
Signalling by TGF-beta ligands through the Smad family of transcription factors is critical for developmental patterning and growth. Disruption of this pathway has been observed in various cancers. In vertebrates, members of the Ski/Sno protein family can act as negative regulators of TGF-beta signalling, interfering with the Smad machinery to inhibit the transcriptional output of this pathway. In some contexts ski/sno genes function as tumour suppressors, but they were originally identified as oncogenes, whose expression is up-regulated in many tumours. These growth regulatory effects and the normal physiological functions of Ski/Sno proteins have been proposed to result from changes in TGF-beta signalling. However, this model is controversial and may be over-simplified, because recent findings indicate that Ski/Sno proteins can affect other signalling pathways. To address this issue in an in vivo context, we have analyzed the function of the Drosophila Ski/Sno orthologue, SnoN. We found that SnoN inhibits growth when overexpressed, indicating a tumour suppressor role in flies. It can act in multiple tissues to selectively and cell autonomously antagonise signalling by TGF-beta ligands from both the BMP and Activin sub-families. By contrast, analysis of a snoN mutant indicates that the gene does not play a global role in TGF-beta-mediated functions, but specifically inhibits TGF-beta-induced wing vein formation. We propose that SnoN normally functions redundantly with other TGF-beta pathway antagonists to finely adjust signalling levels, but that it can behave as an extremely potent inhibitor of TGF-beta signalling when highly expressed, highlighting the significance of its deregulation in cancer cells.
转化生长因子-β（TGF-β）配体通过转录因子Smad家族进行信号传导，这对发育模式形成和生长至关重要。在各种癌症中均观察到该信号通路的破坏。在脊椎动物中，Ski/Sno蛋白家族成员可作为TGF-β信号传导的负调节因子，干扰Smad机制以抑制该信号通路的转录输出。在某些情况下，ski/sno基因发挥肿瘤抑制因子的作用，但它们最初被鉴定为癌基因，其表达在许多肿瘤中上调。有人提出，Ski/Sno蛋白的这些生长调节作用和正常生理功能是由TGF-β信号传导的变化导致的。然而，该模型存在争议且可能过于简化，因为最近的研究结果表明，Ski/Sno蛋白可影响其他信号通路。为了在体内环境中解决这个问题，我们分析了果蝇Ski/Sno直系同源物SnoN的功能。我们发现，SnoN过表达时会抑制生长，表明其在果蝇中具有肿瘤抑制作用。它可在多个组织中发挥作用，选择性地且细胞自主地拮抗来自骨形态发生蛋白（BMP）和激活素亚家族的TGF-β配体的信号传导。相比之下，对snoN突变体的分析表明，该基因在TGF-β介导的功能中并不起全局性作用，而是特异性地抑制TGF-β诱导的翅脉形成。我们提出，SnoN通常与其他TGF-β信号通路拮抗剂发挥冗余功能，以精细调节信号水平，但当高表达时，它可作为TGF-β信号传导的极强抑制剂，这凸显了其在癌细胞中失调的重要性。
