CYTOSKELETAL CONTROL OF GENE-EXPRESSION - DEPOLYMERIZATION OF MICROTUBULES ACTIVATES NF-KAPPA-B

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-B-kappa and induce NFkappaB-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-B-kappa resides in the cytosplasm as a complex with its inhibitor IkappaB. Upon cell stimulation, NF-B-kappa translocates to the nucleus with concomitant degradation of IkappaB. We show that cold-induced depolymerization of microtubules also leads to I kappa B degradation and activation of NF-B-kappa. However, the activated factor remains in the cytoplasm and translocates to the nucleus only upon warming to 37 degrees C, thus revealing two distinct steps in NF-B-kappa activation. These findings establish a new role for NF-B-kappa in sensing changes in the state of the cytoskeleton and converting them to changes in gene activity.