Figure 9

Model for the TNF-dependent activation of proliferation is NSCs. The TNF receptor is depicted in purple in the plasma membrane. Activation induces phosphorylation of IκB-α via IKKα/β complex at ser 32 and 36, which subsequently leads to ubiquitination of IκB by IkB ubiquitin ligase and degradation within the proteasome resulting in nuclear translocation of p50/p65. Transcription of NF-κB target genes such as cyclin D1 is responsible for proliferation and can be repressed by expression of the transdominant negative super-repressor IκB-AA1. In addition, pharmacological blockade of IκB ubiquitin ligase or silencing of IKK-β via siRNA leads to strongly decreased cyclin D1 expression and proliferation of NSCs. In contrast, TGFβ activated kinase-1 (TAK-1) seems to be involved but is not crucial for TNF-mediated NF-κB activation.