Tumor necrosis factor-alpha inhibits Schwann cell proliferation by up-regulating Src-suppressed protein kinase C substrate expression

Src-suppressed protein kinase C substrate (SSeCKS) is a protein kinase C substrate protein, which plays an important role in mitogenic regulatory activity. In the early stage of nerve injury, expression of SSeCKS in the PNS increases, mainly in Schwann cells (SCs). However, the exact function of SSeCKS in the regulation of SC proliferation remains unclear. In this study, we found that tumor necrosis factor-alpha (TNF-alpha) induced both SSeCKS alpha isoform expression and SC growth arrest in a dose-dependent manner. By knocking down SSeCKS alpha isoform expression, TNF-alpha-induced growth arrest in SCs was partially rescued. Concurrently, the expression of cyclin D1 was reduced and the activity of extracellular signal-regulated kinase 1/2 was decreased. A luciferase activity assay showed that cyclin D1 expression was regulated by SSeCKS at the transcription level. In addition, the cell fragments assay and immunofluorescence revealed that TNF-alpha prevented the translocation of cyclin D1 into the nucleus, while knocking down SSeCKS alpha isoform expression prompted cyclin D1 redistribution to the nucleus. In summary, our data indicate that SSeCKS may play a critical role in TNF-alpha-induced SC growth arrest through inhibition of cyclin D1 expression thus preventing its nuclear translocation.