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J. Biol. Chem., Vol. 281, Issue 48, 37142-37149, December 1, 2006

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Loss of Ikk Promotes Migration and Proliferation of Mouse Embryo Fibroblast Cells^*

Fei Chen¹, Yongju Lu, Vince Castranova, Zhiwei Li², and Michael Karin

From the Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505 and the Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093

The IB kinase complex (IKK) is central to the activation of NF-B, a critical transcription factor governing expression of genes involved in cell proliferation and anti-apoptotic responses. Mice with genetic disruptions of the Ikk or Ikk gene loci die during embryogenesis because of severe hepatic apoptosis. We now show that Ikk gene deficiency promotes migration and proliferation of mouse embryo fibroblast cells. Morphological analyses revealed an unusual protrusion of the cytoplasm in Ikk^-/- cells when cultured at a lower density. In a Boyden chamber assay, Ikk^-/- cells exhibited a high rate of invasion and migration. Enhanced formation of actin stress fibers was also observed in the Ikk^-/- cells. Mechanistic studies indicated that IKK affects the expression of proteins involved in the assembly of cytoskeleton and cell movement. Furthermore, re-expression of Ikk and antioxidant treatment in Ikk^-/- 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^-/- cells. These data thus suggest that IKK provides inhibitory signals for cell mobility and growth. Deficiency in the Ikk gene promotes cell mobilization, at least partially, through a ROS-dependent mechanism.

Received for publication, April 14, 2006 , and in revised form, August 15, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Present address: Moffitt Cancer Center and Research Institute, SRB-22344, 3011 West Holly Dr., Tampa, FL 33612.

¹ To whom correspondence should be addressed: PPRB/NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505. Tel.: 304-285-6021; E-mail: lfd3{at}cdc.gov.

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