A role for IkappaB kinase 2 in bipolar spindle assembly.
IkappaB kinase 2 (IKK2 or IKKbeta) is a component of the IKK complex that coordinates the cellular response to a diverse set of extracellular stimuli, including cytokines, microbial infection, and stress. In response to an external stimulus, the complex is activated, resulting in the phosphorylation and subsequent proteasome-mediated degradation of IkappaB proteins. This event triggers the nuclear import of the NF-kappaB transcription factor, which activates the transcription of genes that regulate a variety of fundamental biological processes, including immune response, cell survival, and development. Here, we define an essential role for IKK2 in normal mitotic progression and the maintenance of spindle bipolarity. Chemical and genetic perturbation of IKK2 promotes the formation of multipolar spindles and chromosome missegregation. Depletion of IKK2 results in the deregulation of Aurora A protein stability and coincident hyperactivation of a putative Aurora A substrate, the mitotic motor KIF11. These data support a function for IKK2 as an antagonist of Aurora A signaling during mitosis. Additionally, our results indicate a direct role for IKK2 in the maintenance of genome stability and underscore the potential for oncogenic consequences in targeting this kinase for therapeutic intervention.
Irelan
Jeffrey T
JT
Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
Murphy
Thomas J
TJ
DeJesus
Paul D
PD
Teo
Hsiangling
H
Xu
Dingyue
D
Gomez-Ferreria
Maria A
MA
Zhou
Yingyao
Y
Miraglia
Loren J
LJ
Rines
Daniel R
DR
Verma
Inder M
IM
Sharp
David J
DJ
Tergaonkar
Vinay
V
Chanda
Sumit K
SK
D000782:Aneuploidy; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects / Q000201:enzymology*
D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase