| Transforming growth factor-β (TGF-β) superfamily members are critical regulators of cell proliferation and differentiation, developmental patterning and morphogenesis and disease pathogenesis. Upon stimulation by TGF-β, activated receptors phosphorylate Smad2 and Smad3, resulting in their translocation to the nucleus, association with Smad4 and transcriptional regulation of target genes. Ski and SnoN are related oncoproteins originally discovered based on homology to v-Ski, the transforming protein of the Sloan-Kettering virus. They regulate TGF-β signaling by binding to Smad2 and Smad4 and repressing their ability to activate transcription. Following TGF-β stimulation, SnoN is rapidly degraded by the ubiquitin proteasome pathway providing negative feedback regulation. Overexpression of SnoN and Ski can transform avian fibroblasts and induce muscle differentiation. Mice heterozygous for SnoN and Ski display increased susceptibility to tumorigenesis. Interestingly, elevated expression of Ski and SnoN has been observed in many tumors and may serve as important prognostic markers. Taken together, these studies suggest possible dual functions of these proteins at different stages of tumorigenesis. |
