Microtubule-mediated NF-κB activation in the TNF-α signaling pathway

The microtubule cytoskeleton is known to play a role in cell structure and serve as a scaffold for a variety of active molecules in processes as diverse as motility and cell division. The literature on the role of microtubules in signal transduction, however, is marked by inconsistencies. We have investigated a well-studied signaling pathway, TNF-alpha-induced NF-kappa B activation, and found a connection between the stability of microtubules and the regulation of NF-kappa B signaling in C2C12 myotubes. When microtubules are stabilized by paclitaxel (taxol), there is a strong induction of NF-kappa B even in the absence of TNF-alpha. Although there was no additive effect of taxol and TNF-alpha on NF-kappa B activity suggesting a shared mechanism of activation, taxol strongly induced the NF-kappa B reporter in the presence of a TNF receptor (TNFR) blocking antibody while TNF-alpha did not. Both TNF-alpha and taxol induce the degradation of endogenous I kappa B alpha. and either taxol or TNF-alpha induction of NF-kappa B activity was blocked by inhibitors of NF-kappa B acting at different sites in the signaling pathway. Both TNF-alpha and taxol strongly induce known NF-kappa B chemokine target genes. On the other hand, if microtubules are destabilized by colchicine, then the induction of NF-kappa B by TNF-alpha or taxol is greatly reduced. Taken together, we Surmise that the activity of microtubules is at the level of the TNFR intracellular domain. This phenomenon may indicate a new level of signaling organization in cell biology, actively created by the state of the cytoskeleton, and has ramifications for therapies where microtubule regulating drugs are used. (C) 2009 Elsevier Inc. All rights reserved.