SnoN signaling in proliferating cells and postmitotic neurons

Abstract

The transcriptional regulator SnoN plays a fundamental role as a modulator of transforming growth factor beta (TGFβ)-induced signal transduction and biological responses. In recent years, novel functions of SnoN have been discovered in both TGFβ-dependent and TGFβ-independent settings in proliferating cells and postmitotic neurons. Accumulating evidence suggests that SnoN plays a dual role as a corepressor or coactivator of TGFβ-induced transcription. Accordingly, SnoN exerts oncogenic or tumor-suppressive effects in epithelial tissues. At the cellular level, SnoN antagonizes or mediates the ability of TGFβ to induce cell cycle arrest in a cell-type specific manner. SnoN also exerts key effects on epithelial-mesenchymal transition (EMT), with implications in cancer biology. Recent studies have expanded SnoN functions to postmitotic neurons, where SnoN orchestrates key aspects of neuronal development in the mammalian brain, from axon growth and branching to neuronal migration and positioning. In this review, we will highlight our understanding of SnoN biology at the crossroads of cancer biology and neurobiology.

Figure 1. SnoN functions in TGFβ-induced transcription and cellular responses

a. SnoN promotes TGFβ-induced transcription and biological responses by acting as an adaptor inducing a Smad-SnoN-ING2 multiprotein complex on promoters of TGFβ-responsive genes. b. Sumoylation is critical for the ability of SnoN to inhibit TGFβ-induced EMT. In epithelial cells, the SUMO E3 ligase PIAS1 sumoylates SnoN and thereby maintains the expression of epithelial markers and phenotype. Activation of TGFβ pathway results in the degradation of PIAS1 and subsequent reduction in the level of sumoylated SnoN, thus facilitating EMT.

Figure 2. SnoN has versatile functions in the mammalian brain

a. SnoN promotes axons growth in postmitotic neurons. SnoN associates with the transcriptional coactivator p300 to induce transcription of the Ccd1 gene, which has a critical role in axon growth. SnoN-induced axon growth is controlled by the ubiquitin ligase Cdh1-APC, which is recruited to SnoN by the TGFβ-Smad pathway. b. The SnoN isoforms, SnoN1 and SnoN2, have opposing roles in the coordinate regulation of neuronal branching and migration. SnoN1 promotes neuronal branching and inhibits neuronal migration. SnoN2 inhibits the ability of SnoN1 to control neuronal branching and migration. SnoN1 associates with the transcription FOXO1 to repress the expression of the DCX gene.