Loss of Ikkβ promotes migration and proliferation of mouse embryo fibroblast cells

The I kappa B kinase complex (IKK) is central to the activation of NF-kappa B, a critical transcription factor governing expression of genes involved in cell proliferation and anti-apoptotic responses. Mice with genetic disruptions of the Ikk beta or Ikk gamma gene loci die during embryogenesis because of severe hepatic apoptosis. We now show that Ikk beta gene deficiency promotes migration and proliferation of mouse embryo fibroblast cells. Morphological analyses revealed an unusual protrusion of the cytoplasm in Ikk beta(-/-) cells when cultured at a lower density. In a Boyden chamber assay, Ikk beta(-/-) cells exhibited a high rate of invasion and migration. Enhanced formation of actin stress fibers was also observed in the Ikk beta(-/-) cells. Mechanistic studies indicated that IKK beta affects the expression of proteins involved in the assembly of cytoskeleton and cell movement. Furthermore, re-expression of Ikk beta and antioxidant treatment in Ikk beta(-/-) cells caused a reversal of protrusive phenotype and high motility, respectively. Furthermore, elimination of reactive oxygen species (ROS) blocked expression of snail and subsequently derepressed E-cadherin expression. Although the underlying mechanism is likely entangled and complicated, the data presented indicate that generation of ROS played a key role in the morphological and mobility changes in Ikk beta(-/-) cells. These data thus suggest that IKK beta provides inhibitory signals for cell mobility and growth. Deficiency in the Ikk gamma gene promotes cell mobilization, at least partially, through a ROS-dependent mechanism.