Colorectal cancer
Breast cancer
Lung cancer
Mitosis
2007/10-31/21
Proc
Natl Acad Sci U S A. 2007 Oct 15; [Epub
ahead of print] Irelan JT, Murphy
TJ, Dejesus
PD, Teo H, Xu D, Gomez-Ferreria MA, Zhou
Y, Miraglia LJ, Rines DR, Verma IM, Sharp
DJ, Tergaonkar V, Chanda SK. Genomics Institute of the Novartis Research Foundation, 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. PMID: 17939994 [PubMed
- as supplied by publisher Proc
Natl Acad Sci U S A. 2005 Aug 30;102(35):12425-30.
Epub 2005 Aug 22. Li
Q, Lu
Q, Bottero V, Estepa G, Morrison
L, Mercurio F, Verma IM. The Salk
Institute for Biological Studies, IkappaB
kinase (IKK) complex plays a key regulatory role
in macrophages for NF-kappaB activation during both
innate and adaptive immune responses. Because IKK1-/- mice died at birth,
we differentiated functional macrophages from embryonic day 15.5 IKK1
mutant embryonic liver. The embryonic liver-derived macrophage (ELDM)
showed enhanced phagocytotic clearance of
bacteria, more efficient antigen-presenting capacity, elevated secretion of
several key proinflammatory cytokines and chemokines, and known NFkappaB
target genes. Increased NFkappaB activity in IKK1
mutant ELDM was the result of prolonged degradation of IkappaBalpha
in response to infectious pathogens. The delayed restoration of IkappaBalpha in pathogen-activated IKK1-/- ELDM was a
direct consequence of uncontrolled IKK2 kinase
activity. We hypothesize that IKK1 plays a checkpoint role in the proper control
of IkappaBalpha kinase
activity in innate and adaptive immunity. PMID: 16116086 [PubMed
- indexed for MEDLINE Curr Biol. 2005 Jul 26;15(14):1291-5. Correa
RG, Matsui
T, Tergaonkar V, Rodriguez-Esteban
C, Izpisua-Belmonte JC, Verma IM. The Salk
Institute for Biological Studies, The IkappaB
kinase (IKK) activity is critical for processing IkappaB inhibitory proteins and activating the NF-kappaB signaling, which is involved in a series of
physiological and developmental steps in vertebrates. The IKK activity resides
in two catalytic subunits, IKK1 and IKK2, and two regulatory subunits, NEMO
and ELKS. IKK2 is the major cytokine-responsive IkappaB
kinase because depletion of IKK1 does not
interfere with the IKK activity. In fact, IKK1-/- mice display morphological
abnormalities that are independent of its kinase
activity and NF-kappaB activation. Hence, using zebrafish (Danio rerio) as a model, we examined the evolutionary role of
IKK1 in modulating NF-kappaB. Ikk1-/- zebrafish embryos present head and tail malformations
and, surprisingly, show upregulation of NF-kappaB-responsive genes and increased NF-kappaB-dependent apoptosis. Overexpression
of ikk1 leads to midline structure defects that resemble NF-kappaB blockage in vivo. Zebrafish
Ikk1 forms complexes with NEMO that represses NF-kappaB
in vertebrate cells. Indeed, truncation of its NEMO binding domain (NBD)
restores NF-kappaB-dependent transcriptional
activity and, consequently, the ikk1-overexpressing phenotype. Here, we
report that Ikk1 negatively regulates NF-kappaB
by sequestering NEMO from active IKK complexes, indicating that IKK1 can
function as a repressor of NF-kappaB. PMID: 16051172 [PubMed
- indexed for MEDLINE
A role for I{kappa}B kinase 2 in bipolar spindle assembly.
Enhanced NF-kappaB activation and cellular function in macrophages
lacking IkappaB kinase
1 (IKK1).
Zebrafish IkappaB kinase 1 negatively
regulates NF-kappaB activity.
]