Cytoskeletal control of gene expression: Depolymerization of microtubules activates NF-κB

Abstract

Cell shape changes exert specific effects on gene expression. It has been speculated that the cytoskeleton is responsible for converting changes in the cytoarchitecture to effects on gene transcription. However, the signal transduction pathways responsible for cytoskeletal-nuclear communication remained unknown. We now provide evidence that a variety of agents and conditions that depolymerize microtubules activate the sequence-specific transcription factor NF-κB and induce NFκB-dependent gene expression. These effects are caused by depolymerization of microtubule because they are blocked by the microtubule-stabilizing agent taxol. In nonstimulated cells, the majority of NF-κB resides in the cytosplasm as a complex with its inhibitor IκB. Upon cell stimulation, NF-κB translocates to the nucleus with concomitant degradation of IκB. We show that cold-induced depolymerization of microtubules also leads to IκB degradation and activation of NF-κB. However, the activated factor remains in the cytoplasm and translocates to the nucleus only upon warming to 37°C, thus revealing two distinct steps in NF-κB activation. These findings establish a new role for NF-κB in sensing changes in the state of the cytoskeleton and converting them to changes in gene activity.