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Loss of IkkB promotes migration and proliferation of mouse embryo fibroblast cells.

Authors
Chen-F; Lu-Y; Castranova-V; Li-Z; Karin-M
Source
J Biol Chem 2006 Dec; 281(48):37142-37149
NIOSHTIC No.
20031275
Abstract
The IkappaB kinase complex (IKK) is central to the activation of NF-kappaB, a critical transcription factor governing expression of genes involved in cell proliferation and anti-apoptotic responses. Mice with genetic disruptions of the Ikkbeta or Ikkgamma gene loci die during embryogenesis because of severe hepatic apoptosis. We now show that Ikkbeta gene deficiency promotes migration and proliferation of mouse embryo fibroblast cells. Morphological analyses revealed an unusual protrusion of the cytoplasm in Ikkbeta(-/-) cells when cultured at a lower density. In a Boyden chamber assay, Ikkbeta(-/-) cells exhibited a high rate of invasion and migration. Enhanced formation of actin stress fibers was also observed in the Ikkbeta(-/-) cells. Mechanistic studies indicated that IKKbeta affects the expression of proteins involved in the assembly of cytoskeleton and cell movement. Furthermore, re-expression of Ikkbeta and antioxidant treatment in Ikkbeta(-/-) 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 Ikkbeta(-/-) cells. These data thus suggest that IKKbeta provides inhibitory signals for cell mobility and growth. Deficiency in the Ikkbeta gene promotes cell mobilization, at least partially, through a ROS-dependent mechanism.
Keywords
Laboratory-animals; Animal-studies; Animals; Genes; Genetics; Mutation; Mutagens; Antioxidants; Antioxidation; Free-radicals; Free-radical-generation
Contact
PPRB/NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505
CODEN
JBCHA3
Publication Date
20061201
Document Type
Journal Article
Email Address
lfd3@cdc.gov
Fiscal Year
2007
NTIS Accession No.
NTIS Price
Issue of Publication
48
ISSN
0021-9258
NIOSH Division
HELD
Source Name
Journal of Biological Chemistry
State
WV
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