SnoN expression is subjected to stringent regulation in normal mammalian cells at the levels of protein stability, transcriptional activation, and post-translational modification [11
]. SnoN transcription can be induced by oxidative stress [29
] and tissue injury and upon stimulation with certain growth factors and cytokines (). The observation that SnoN transcription is upregulated at late pregnancy and early lactation suggests that it might also be regulated by the pregnancy hormones [19
]. During liver regeneration following injury, SnoN expression is activated, possibly mediated by the hepatocyte growth factor (HGF) [30
]. SnoN expression is also altered during obstructive neuropathy [32
]. The factors and pathways responsible for SnoN induction during these processes have not been determined.
SnoN transcription is potently and rapidly induced by TGF-β through a direct binding of the Smad2/Smad4 complex to the Smad binding elements in the snoN
]. TGF-β also regulates SnoN stability through an ubiquitin-dependent proteasome degradation pathway. Several E3 ubiquitin ligases that interact with the R-Smads have been shown to be recruited to SnoN for its ubiquitination, including the Smad ubiquitin regulatory factor (Smurf 2), the Anapahase promoting complex (APC/C) and Arkadia [11
]. At the post-translational level, SnoN can be modified by Sumoylation and phosphorylation. The SUMO E3 ligase PIAS has been shown to modify lysines 50 and 383 of SnoN in a TGF-β-independent manner [24
]. SnoN can also be phosphorylated by the TGF-β-activated kinase (TAK1) on serines 115 and 117, and/or threonine 119 [36
]. The functional significance of these modifications has not been fully understood.
Intracellular localization constitutes another layer of SnoN regulation. Although originally identified as a nuclear protein in transformed cell lines and fibroblasts [3
], SnoN is predominantly cytoplasmic in normal mammary gland, epidermis, esophagus, and liver. The predominant cytoplasmic localization is also found in primary mammary epithelial cells, keratinocytes, hepatocytes, and untransformed mammary epithelial cell lines [19••
]. The mechanism that regulates SnoN localization has not been defined.